EP1534825A2

EP1534825A2 - Human analogs of murine deubiquitinating protease genes

Info

Publication number: EP1534825A2
Application number: EP03711195A
Authority: EP
Inventors: Chang Hahn; Hong Liu
Original assignee: Aventis Pharmaceuticals Inc
Current assignee: Aventis Pharmaceuticals Inc
Priority date: 2002-02-22
Filing date: 2003-02-20
Publication date: 2005-06-01
Also published as: MXPA04007760A; AU2003215370A1; EP1534825A4; AU2003215370B2; CA2476770A1; BR0307895A; IL163528A0; WO2003072724A2; WO2003072724A3

Abstract

The present invention is directed to human analogs of murine hematopoetic-specific, cytokine-inducible deubiquinating proteases ('DUBs') clustered on chromosomes 4 and 8 and their respective regulatory regions. The nucleotides or proteins encoded thereby my be used in assays to identify inhibitors of human DUBs.

Description

Human Analogs of Murine Deubiquitinating Protease Genes

Background of the Invention The role of ubiquitin in protein degradation was discovered and the main enzymatic reactions of this system elucidated in biochemical studies in a cell-free system from reticulocytes. In this system, proteins are targeted for degradation by covalent ligation to ubiquitin, a 76-amino-acid-residue protein. Briefly, ubiquitin-protein ligation requires the sequential action of three enzymes. The C-terminal Gly residue of ubiquitin is activated in an ATP -requiring step by a specific activating enzyme, El (Step 1). This step consists of an intermediate formation of ubiquitin adenylate, with the release of PP„ followed by the binding of ubiquitin to a Cys residue of El in a thiolester linkage, with the release of AMP. Activated ubiquitin is next transferred to an active site Cys residue of a ubiquitin-carrier protein, E2 (Step 2). In the third step catalyzed by a ubiquitin-protein ligase or E3 enzyme, ubiquitin is linked by its C-terminus in an amide isopeptide linkage to an -amino group of the substrate protein's Lys residues (Step 3).

Proteins ligated to polyubiquitin chains are usually degraded by the 26S proteasome complex that requires ATP hydrolysis for its action. The 26S proteasome is formed by an ATP-dependent assembly of a 20S proteasome, a complex that contains the protease catalytic sites, with 19S "cap" or regulatory complexes. The 19S complexes contain several ATPase subunits and other subunits that are presumably involved in the specific action of the 26S proteasome on ubiquitinylated proteins. The roles of ATP in the assembly of the 26S proteasome complex and in its proteolytic action are not understood. The action of the 26S proteasome presumably generates several types of products: free peptides, short peptides still linked to ubiquitin via their Lys residues, and polyubiquitin chains (Step 4). The latter two products are converted to free and reusable ubiquitin by the action of ubiquitin-C-terminal hydrolases or isopeptidases (Steps 5 and 6). Some isopeptidases may also disassemble certain ubiquitin-protein conjugates (Step 7) and thus prevent their proteolysis by the 26S proteasome. The latter type of isopeptidase action may have a correction function to salvage incorrectly ubiquitinylated proteins or may have a regulatory role. Short peptides formed by the above processes can be further degraded to free amino acids by cytosolic peptidases (Step 8). Ubiquitin-mediated degradation of protein is involved in various biological processes. The selective and programmed degradation of cell-cycle regulatory proteins, such as cyclins, inhibitors of cyclin-dependent kinases, and anaphase inhibitors are essential events in cell- cycle progression. Cell growth and proliferation are further controlled by ubiquitin-mediated degradation of tumor suppressors, protooncogenes, and components of signal transduction systems. The rapid degradation of numerous transcriptional regulators is involved in a variety of signal transduction processes and responses to environmental cues. The ubiquitin system is clearly involved in endocytosis and down-regulation of receptors and transporters, as well as in the degradation of resident or abnormal proteins in the endoplasmic reticulum. There are strong indications for roles of the ubiquitin system in development and apoptosis, although the target proteins involved in these cases have not been identified. Dysfunction in several ubiquitin-mediated processes causes pathological conditions, including malignant transformation.

Our knowledge of different signals in proteins that mark them for ubiquitinylation is also limited. Recent reports indicate that many proteins are targeted for degradation by phosphorylation. It was observed previously that many rapidly degraded proteins contain PEST elements, regions enriched in Pro, Glu, Ser, and Thr residues. More recently, it was pointed out that PEST elements are rich in S/TP sequences, which are minimum consensus phosphorylation sites for Cdks and some other protein kinases. Indeed, it now appears that in several (though certainly not all) instances, PEST elements contain phosphorylation sites necessary for degradation. Thus multiple phosphorylations within PEST elements are required for the ubiquitinylation and degradation of the yeast Gl cyclins Cln3 and Cln2, as well as the Gcn4 transcriptional activator. Other proteins, such as the mammalian Gl regulators cyclin E and cyclin DI , are targeted for ubiquitinylation by phosphorylation at specific, single sites. In the case of the IkBα inhibitor of the NF-kB transcriptional regulator, phosphorylation at two specific sites, Ser-32 and Ser-36, is required for ubiquitin ligation. β-cateinin, which is targeted for ubiquitin-mediated degradation by phosphorylation, has a sequence motif similar to that of IkBα around these phosphorylation sites. However, the homology in phosphorylation patterns of these two proteins is not complete, because phosphorylation of other sites of β-catenin is also required for its degradation. Other proteins targeted for degradation by phosphorylation include the Cdk inhibitor Siclp and the ST ATI transcription factor. Though different patterns of phosphorylation target different proteins for degradation, a common feature appears to be that the initial regulatory event is carried out by a protein kinase, while the role of a ubiquitin ligase would be to recognize the phosphorylated form of the protein substrate. It further appears that different ubiquitin ligases recognize different phosphorylation patterns as well as additional motifs in the various protein substrates. However, the identity of such E3s is unknown, except for some PULC-type ubiquitin ligases that act on some phosphorylated cell-cycle regulators in the budding yeast. The multiplicity of signals that target proteins for ubiquitin-mediated degradation (and of ligases that have to recognize such signals) is underscored by observations that the phosphorylation of some proteins actually prevents their degradation. Thus the phosphorylation of the c-Mos protooncogene on Ser3 and the multiple phosphorylations of c-Fos and c-Jun protooncogenes at multiple sites by MAP kinases suppress their ubiquitinylation and degradation.

In addition to the families of enzymes involved in conjugation of ubiquitin, a very large family of deubiquitinating enzymes has recently been identified from various organisms. These enzymes have several possible functions. First, they may have peptidase activity and cleave the products of ubiquitin genes. Ubiquitin is encoded by two distinct classes of genes. One is a polyubiquitin gene, which encodes a linear polymer of ubiquitins linked through peptide bonds between the C-terminal Gly and N-terminal Met of contiguous ubiquitin molecules. Each copy of ubiquitin must be released by precise cleavage of the peptide bond between Gly-76-Met-l of successive ubiquitin moieties. The other class of ubiquitin genes encodes ubiquitin C-terminal extension proteins, which are peptide bond fusions between the C-terminal Gly of ubiquitin and N-terminal Met of the extension protein. To date, the ^' extensions described are ribosomal proteins consisting of 52 or 76-80 amino acids. These ubiquitin fusion proteins are processed to yield ubiquitin and the corresponding C-terminal extension proteins. Second, deubiquitinating enzymes may have isopeptidase activities. When a target protein is degraded, deubiquitinating enzymes can cleave the polyubiquitin chain from the target protein or its remnants. The polyubiquitin chain must also be disassembled by deubiquitinating enzymes during or after proteolysis by the 26 S proteasome, regenerating free monomeric ubiquitin. In this way, deubiquitinating enzymes can facilitate the ability of the 26 S proteasome to degrade ubiquitinated proteins. Third, deubiquitinating enzymes may hydrolyze ester, thiolester, and amide linkages to the carboxyl group of Gly-76 of ubiquitin. Such nonfunctional linkages may arise from reactions between small intracellular compounds such as glutathione and the E1-, E2-, or E3-ubiquitin thiolester intermediates. Fourth, deubiquitinating enzymes may compete with the conjugating system by removing ubiquitin from protein substrates, thereby rescuing them from degradation or any other function mediated by ubiquitination. Thus generation of ubiquitin by deubiquitinating enzymes from the linear polyubiquitin and ubiquitin fusion proteins and from the branched polyubiquitin ligated to proteins should be essential for maintaining a sufficient pool of free ubiquitin. Many deubiquitinating enzymes exist, suggesting that these deubiquitinating enzymes recognize distinct substrates and are therefore involved in specific cellular processes. Although there is recent evidence to support such specificity of these deubiquitinating enzymes, the structure- function relationships of these enzymes remain poorly studied.

Deubiquitinating enzymes can be divided broadly on the basis of sequence homology into two classes, the ubiquitin-specific processing protease (UBP or USP, also known as type 2 ubiquitin C-terminal hydrolase (type 2 UCH)) and the UCH, also known as type 1 UCH). UCH (type 1 UCH) enzymes hydrolyze primarily C-terminal esters and amides of ubiquitin but may also cleave ubiquitin gene products and disassemble polyubiquitin chains . They have in common a 210-amino acid catalytic domain, with four highly conserved blocks of sequences that identify these enzymes. They contain two very conserved motifs, the CYS and HIS boxes. Mutagenesis studies revealed that the two boxes play important roles in catalysis. Some UCH enzymes have significant C-terminal extensions. The functions of the C-terminal extensions are still unknown but appear to be involved in proper localization of the enzyme. The active site of these UCH enzymes contains a catalytic triad consisting of cysteine, histidine, and aspartate and utilizes a chemical mechanism similar to that of papain. The crystal structure of one of these, UCH-L3, has been solved at 1.8 A resolution. The enzyme comprises a central antiparallel β-sheet flanked on both sides by helices. The β-sheet and one of the helices are similar to those observed in the thiol protease cathepsin B. The similarity includes the three amino acid residues that comprise the active site, Cys⁹⁵, His¹ , and Asp¹⁸⁴. The active site appears to fit the binding of ubiquitin that may anchor also at an additional site. The catalytic site in the free enzyme is masked by two different segments of the molecule that limit nonspecific hydrolysis and must undergo conformational rearrangement after substrate binding.

UBP (type 2 UCH) enzymes are capable of cleaving the ubiquitin gene products and disassembling polyubiquitin chains after hydrolysis. It appears that there is a core region of about 450 amino acids delimited by CYS and HIS boxes. Many of these isoforms have N- terminal extensions and a few have C-terminal extensions. J-n addition, there are variable sequences in the core region of many of the isoforms. The functions of these divergent sequences remain poorly characterized. Another interesting function of specific UBPs is the regulation of cell proliferation. It was observed that cytokines induced in T-cells specific deubiquitinating enzymes (DUBs), termed DUB-1 and DUB-2. DUB-1 is induced by stimulation of the cytokine receptors for IL-3, IL-5, and GM-CSF, suggesting a role in its induction for the ^β-common (betac) subunit of the interieukin receptors. Overexpression of a dominant negative mutant of JAK2 inhibits cytokine induction of DUB-1, suggesting that the regulation of the enzyme is part of the cell response to the JAK/STAT signal transduction pathway. Continued expression of DUB-1 arrests cells at Gi; therefore, the enzyme appears to regulate cellular growth via control of the G_o-Gι transition. The catalytic conserved Cys residue of the enzyme is required for its activity. DUB-2 is induced by IL-2 as an immediate early (IE) gene that is down-regulated shortly after the initiation of stimulation. The function of this enzyme is also obscure. It may stimulate or inhibit the degradation of a critical cell-cycle regulator.

Cytokines, such as interleukin-2 (IL-2), activate intracellular signaling pathways via rapid tyrosine phosphorylation of their receptors, resulting in the activation of many genes involved in cell growth and survival. The deubiquitinating enzyme DUB-2 is induced in response to IL-2 and is expressed in human T-cell lympho tropic virus-I (HTLV-1)- transformed T cells that exhibit constitutive activation of the IL-2 JAK/STAT (signal transducers and activators of transcription) pathway, and when expressed in Ba/F3 cells DUB- 2 markedly prolonged IL-2-induced STAT5 phosphorylation. Although DUB-2 does not enhance IL-2-mediated proliferation, when withdrawn from growth factor, cells expressing DUB-2 had sustained STAT5 phosphorylation and enhanced expression of IL-2-induced genes cis and c-myc. DUB-2 expression markedly inhibited apoptosis induced by cytokine withdrawal allowing cells to survive. Therefore, DUB-2 has a role in enhancing signaling through the JAK/STAT pathway, prolonging lymphocyte survival, and, when constitutively expressed, may contribute to the activation of the JAK/STAT pathway observed in some transformed cells. (Migone, T.-S., et al., Blood. 2001;98:1935-1941).

Protein ubiquitination is an important regulator of cytokine-activated signal transduction pathways and hematopoietic cell growth. Protein ubiquitination is controlled by the coordinate action of ubiquitin-conjugating enzymes and deubiquitinating enzymes. Recently a novel family of genes encoding growth-regulatory deubiquitinating enzymes (DUB-1 and DUB-2) has been identified. DUBs are immediate-early genes and are induced rapidly and transiently in response to cytokine stimuli. By means of polymerase chain reaction amplification with degenerate primers for the DUB-2 complementary DNA, 3 murine bacterial artificial chromosome (BAC) clones that contain DUB gene sequences were isolated. One BAC contained a novel DUB gene (DUB-2 A) with extensive homology to DUB-2. Like DUB- 1 and DUB-2, the DUB-2 A gene consists of 2 exons. The predicted DUB-2 A protein is highly related to other DUBs throughout the primary amino acid sequence, with a hypervariable region at its C-terminus. In vitro, DUB-2 A had functional deubiquitinating activity; mutation of its conserved amino acid residues abolished this activity. The 5' flanking sequence of the DUB-2A gene has a hematopoietic-specific functional enhancer sequence. It is proposed that there are at least 3 members of the DUB subfamily (DUB-1, DUB-2, and DUB-2 A) and that different hematopoietic cytokines induce specific DUB genes, thereby initiating a cytokine- specific growth response. (Baek , K.-H., et al, Blood. 2001;98:636-642).

Protein ubiquitination also serves regulatory functions in the cell that do not involve proteasome-mediated degradation. For example, Hicke and Riezman have recently demonstrated ligand-inducible ubiquitination of the Ste2 receptor in yeast. Ubiquitination of the Ste2 receptor triggers receptor endocytosis and receptor targeting to vacuoles, not proteasomes. Also, Chen et al. have demonstrated that activation of the IB kinase requires a rapid, inducible ubiquitination event. This ubiquitination event is a prerequisite for the specific phosphorylation of IB and does not result in subsequent proteolysis of the kinase complex. The ubiquitination of Ste2 and IB kinase appears reversible, perhaps resulting from the action of a specific deubiquitinating enzyme.

A large superfamily of genes encoding deubiquitinating enzymes, or UBPs, has recently been identified. UBPs are ubiquitin-specific thiol-proteases that cleave either linear ubiquitin precursor proteins or post-translationally modified proteins containing isopeptide ubiquitin conjugates. The large number of UBPs suggests that protein ubiquitination, like protein phosphorylation, is a highly reversible process that is regulated in the cell. Interestingly, UBPs vary greatly in length and structural complexity, suggesting functional diversity. While there is little amino acid sequence similarity throughout their coding region, sequence comparison reveals two conserved domains. The Cys domain contains a cysteine residue that serves as the active enzymatic nucleophile. The His domain contains a histidine residue that contributes to the enzyme's active site. More recent evidence demonstrates six homology domains contained by all members of the ubp superfamily. Mutagenesis of conserved residues in the Cys and His domains has identified several residues that are essential for UBP activity.

Recently, a growth regulatory deubiquitinating enzyme, DUB-1, that is rapidly induced in response to cytokine receptor stimulation was identified. DUB-1 is specifically induced by the receptors for IL-3, granulocyte macrophage-colony-stimulating factor, and IL-5, suggesting a specific role for the c subunit shared by these receptors. In the process of cloning t eDUB-l gene, a family of related, cross-hybridizing DUB genes was identified. From this, other DUB genes might be induced by different growth factors. Using this approach, an IL-2- inducible DUB enzyme, DUB-2 and closely related DUB-2a were identified. DUB-1 and DUB-2 are more related to each other than to other members of the ubp superfamily and thereby define a novel subfamily of deubiquitinating enzymes.

Hematopoietic-specific, cytokine induced DUBs in murine system have shown to prolong cytokine receptor, see Migone, T. S., et αl (2001). The deubiquitinating enzyme DUB-2 prolongs cytokine-induced signal transducers and activators of transcription activation and suppresses apoptosis following cytokine withdrawal, Blood 98, 1935-41; Zhu, Y., et al., (1997). DUB-2 is a member of a novel family of cytokine-inducible deubiquitinating enzymes, J Biol Chem 272, 51-7 and Zhu, Y., et al, (1996). The murine DUB-1 gene is specifically induced by the betac subunit of interieukin- 3 receptor, Mol Cell Biol 16, 4808- 17.). These effects are likely due to the deubiquitination of receptors or other signaling intermediates by DUB-1 or DUB-2, murine analogs of hDUBs. Inhibition of hDUBs may achieve downregulation of specific cytokine receptor signaling, thus modulating specific immune responses.

Cytokines regulate cell growth by inducing the expression of specific target genes. A recently identified a cytokine-inducible, immediate-early gene, DUB-1, encodes a deubiquitinating enzyme with growth regulatory activity. In addition, a highly related gene, DUB-2, that is induced by interleukin-2 was identified. The DUB-2 mRNA was induced in T cells as an immediate-early gene and was rapidly down-regulated. Like DUB-1, the DUB-2 protein had deubiquitinating activity in vitro. When a conserved cysteine residue of DUB-2, required for ubiquitin-specific thiol protease activity, was mutated to serine (C60S), deubiquitinating activity was abolished. DUB-1 and DUB-2 proteins are highly related throughout their primary amino acid sequence except for a hypervariable region at their COOH terminus. Moreover, the DUB genes co-localize to a region of mouse chromosome 7, suggesting that they arose by a tandem duplication of an ancestral DUB gene. Additional DUB genes co-localize to this region, suggesting a larger family of cytokine-inducible DUB enzymes. We propose that different cytokines induce specific DUB genes. Each induced DUB enzyme thereby regulates the degradation or the ubiquitination state of an unknown growth regulatory factor, resulting in a cytokine-specific growth response. On the basis of these structural criteria, additional members of the DUB subfamily can be identified in the GenBank™. The highest degree of homology is in the Cys and His domains. Additionally, this putative human DUB protein contains a Lys domain (amino acids 400-410) and a hypervariable region (amino acids 413-442).

Murine DUB (mDUB) subfamily members differ from other UBPs by functional criteria as well. mDUB subfamily members are cytokine-inducible, immediate-early genes and may therefore play regulatory roles in cellular growth or differentiation. Also, DUB proteins are unstable and are rapidly degraded by ubiquitin-mediated proteolysis shortly after their induction.

mDUB reports demonstrate that specific cytokines, such as IL-2 and IL-3, induce specific deubiquitinating enzymes (DUBs). DUB proteins may modify the ubiquitin- proteolytic pathway and thereby mediate specific cell growth or differentiation signals. These modifications are temporally regulated. The DUB-2 protein, for instance, is rapidly but transiently induced by IL-2. Interference of DUB enzymes with specific isopeptidase inhibitors may block specific cytokine signaling events.

Defensins constitute a major family of antimicrobial peptides in mammals. Depending on the distribution of the cysteines and the linkages of the disulfide bonds, human defensins can be divided into two categories: α-defensins, which can be found in granulocytes and in epithelial cells of the small intestine, and β-defensins, which are expressed by epithelial cells and leukocytes including macrophages. Some defensins are expressed constitutive manner in granulocytes and epithelial cells where as others are induces by either exposure to microbial pathogens or pro-inflammatory cytokines such as IL-1 β, TNF-α and interferon-γ. The genes coding for human defensins are clustered within 1 Mb segment on chromosome 8P23, and it has been suggested that β-defensins may predate the a-defensin family during recent gene amplification since α-defensin cannot be detected even in many mammalians including cow. Cow has at least 13 β-defensins but no α-defensin. β-defensins contribute to early host defense against several bacterial and fungal pathogens, as an important mechanism of innate immune response. Beside this antimicrobial activity, a chemoattractant activity on both immature dentritic cells and memory T cells, as well as monocytes, has been recently described, demonstrating that β-defensins may promote both innate and adaptive immune response.

Summary of the Invention

The present invention is directed to analogs of murine DUBs, hematopoietic-specific, cytokine-inducible deubiquitinating proteases found as a cluster of genes on chromosomes 4 and 8 and respective regulatory regions. Eleven novel human DUBs and four potential genes that express truncated form of DUBs not previously reported in public databases were identified by searching human genome database using murine DUB-1 and DUB-2 sequences. These genes share open reading frames (ORFs) that are 88 to 99% amino acid identity to each other, when gaps caused by deletion and N-terminal and/or C-terminal extension was not counted as mismatch, and exhibit approximately 50% identity to murine DUBs. Eight of eleven ORFs generate a protein of 530 amino acids. Two ORFs (hDUB8.3 and hDUB8.11) have internal in- frame deletions such that the genes are capable of generating 497 and 417 amino acid long polypeptides, respectively. One ORF (hDUB4.5) exhibits extension at both 5' and 3' end of the ORF so that the gene is capable of expressing 574 amino acid long polypeptide. Surprisingly, this 5' extension results in specific pro-polypeptide sequence that can direct polypeptide targeting to the mitochondria. Furthermore, the respective regulatory regions, putative promoters, of these genes also share close to 90% identity each other suggesting that their expression is coordinated. In addition, we found that two of these genes can be expressed under the control of separate promoters that can be controlled independently and expressing potentially distinctive protein products.

Manipulation of these gene products by small molecular compounds can (1) reduce inflammation by regulating proinflammatory cytokine signaling, (2) modulate autoimmune diseases by regulating cytokine receptor signaling that are critical for lymphocytes proliferation, and (3) immune over-reaction during infection using above mechanisms.

Two of cluster genes (hDUB4.1 and hDUB4.2) possesses two distinctive promoter domains in front of their ORFs such that they can be regulated independently in their transcription potential. The longer transcripts of these ORFs (called hDUB4.1a and hDUB4.2a) has 12 and 4 exons respectively and capable of generating 1016 and 1021 amino acid long polypeptides, respectively. These polypeptides share C-terminal 530 amino acids with their shorter form that can be expressed separately from independent promoters (called hDUB4.1b and hDUB4.2b, respectively). In addition, two other ORFs are capable of generating longer than 530 amino acid polypeptides (hDUB4.10 and hDUB4.11). Remarkably, these two deduced polypeptides shares significant homology within portion of N-terminal portions (I added alignment file of these at the end of sequence file). Three of the ORFs (hDUB4.5, 4.8, and 8.2) has N-terminal insertion that is typical for mitochondria targeting sequence. An alignment of these sequences is provide in the Tables. The promoter sequences defined as upstream of initiation ATG of the ORF exhibit remarkable level of homology each other except that of hDUB4.1a. The sequence identity among all promoter sequences except that of hDUB4.1a is approximately 90% in 2000 base pair span upstream of initiation ATG. Two of the promoter sequences (hDUB8.3 and 8.11) have 334 nucleotides insertion at approximately 1000 base pair upstream of initiation ATG. Interestingly, hDUB8.3 and hDUB8.11 are the only ones with shorter ORFs due to the internal deletions. In addition to these ORFs, there are 5 ORFs that are capable of expressing polypeptides (hDUB4.4, hDUB4.9, hDUB8.2, hDUB8.9, and hDUB8.10) that share initiation codon with other 530 amino acid long polypeptides but terminate prematurely due to the in frame termination sequences. These also shares significant homology upstream of ATG initiation codon suggesting they may expressed as truncated proteins, potential regulatory functions. All 11 hDUB8 genes are clustered with the defensin clusters within 2 Mb region in 8P23, implying that both acquisition and amplification are relatively recent event, perhaps during mammalian evolution. It is of interest that hDUB4 gene cluster is also in highly amplified cluster region of chromosome 4P16 that is yet to be assigned in chromosome location. These data suggest that hDUB4s and hDUBδs are within very dynamic region of the human chromosomes (both 4pl6 and 8p23) that are undergoing volatile amplifications. The data also suggest that expression of hDUB8 may also be coordinated in conjunction with defensins that are critical components of innate immune response and inflammation.

Search methods for identifying human analogs of niDUBs:

In order to identify human analogs of mDUBl, -2, -2A, mDUBl (U41636), mDUB2

(NM H0089), and mDUB2A (AF393637) DNA sequences were used to search against Ensembl entire "golden path" (as contigs) using Ensembl blast search engine (http://www.ensembl.org/perl/blastview). All three mDUBs have significant alignments with contig AC083981, AF252831, AF228730, AF252830, AC068974 on chromosome 8 with the high score above 2000 and the probability less than e-87. In order to find all the homolog genes in the genome, exhaust search was performed using genomic aligned sequence to search against the "golden path" contigs. Two more contigs were found to have significant alignment that has probability less than e-100: one is AC074340 on chromosome 8 and the other is AC022770 on chromosome 4.

DNA sequences for contig AC083981, AF252831, AF228730, AF252830, AC068974, AC074340 and AC022770 were downloaded from Ensembl and gene annotation for each contig was performed using GenScan gene annotation program. Genes having homolog with mDUBs were named in sequence based on their locations on chromosomes. For example, hDUB8.1 was derived from AF228730, 8.2, 8.3 were derived from AF252830, 8.5 were derived from AC074340, 8.6 were derived from AF252831, 8.7, 8.8 and 8.9 were derived from AC083981, and 8.10 and 8.11 were derived from AC068974. hDUB4.1, 4.2, 4.3, 4.4, 4.5 were derived from AC022770 on chromosome 4.

Using these hDUB4s and hDUB8s, both Ensemble and NCBI blast search was performed. Further contig NT_028165 that covers chromosome 4 was identified. From this and already assembled chromosome 4pl6.1 region, further annotation was performed using GenScan gene annotation program. From this we identified hDUB4.6, 4.1, 4.8, 4.9, 4.10, and 4.11. Analysis of the hDUB gene clusters in chromosome 4 reveals that at least five ORFs in an unmapped cOntig (AC022770) were identified by nucleotide homology search with murine DUBl and 2. At least four out of five ORFs share core 530 amino acid sequences. Two ORFs (hDUB4.1 and hDUB4.2) are multi-exon ORFs that extend N-terminal part of polypeptides that shares minimal sequence identity. However, there is a conserved putative promoter sequences that encompass over 2,000 bases in the intron region proximal to the last exon that is conserved among all 5 genes. Three of the ORFs (hDUB4.5, 4.8, and 8.2) has N- terminal insertion that is typical for mitochondria targeting sequence. The hDUB genes cluster in 4P16 of the human chromosome, which is an unmapped part of the human chromosome.

Analysis of the hDUB gene clusters in chromosome 8 reveals that at least eleven ORFs in six different contigs (AC068974, AC074340, AC083981, AF228730, AF252830, and AF252831) were identified by nucleotide homology search with murine DUBl and 2. At least seven out of eleven ORFs share significant identities with similar length. There are conserved putative promoter sequences that encompass over 2,000 bases in all 11 genes. The hDUB genes cluster in 8P23.1 of the human chromosome and clustered with defensin molecules (at lease 9 defensins are clustered with hDUB8s) and the whole domain belongs the olfactory GPCR cluster.

Analysis of the deduced amino acid sequences of the hDUBs reveals polypeptides consistent with mDUBs, which contain highly conserved Cys and His domains that are likely to form the enzyme's active site. The putative active site nucleophile of mDUB-2 is a cysteine residue (Cys^"60) in the Cys domain. Both mDUB-1 and mDUB-2 have a lysine rich region (Lys domain; amino acids 374-384 of mDUB-2) and a short hypervariable region (amino acids 385- 451 of mDUB-2), in which the mDUB-1 and mDUB-2 sequences diverge considerably. The hypervariable (HV) region of mDUB-2 contains a duplication of the eight-amino acid sequence: PQEQNHQK.

TaqMan real time PCR analysis of expression ofhDUB4s and hDUB8s in human immunocytes upon various stimulation Protocol of reverse transcription (RT) from total cellular RNA using random hexamer as primer (using TaqMan Reverse Transcription Reagents Cat# N808-0234)

1 ug of total RNA preparation in 100 ul of lxTaqMan RT Buffer Mix, 5.5mM MgCl₂ , 0.5 mM dNTPs, 2.5 uM Random Hexamers, 40 U RNAse inhibitor, 125U Multiscribe Reverse Transcriptase. Mix by pipeting up and down. Incubate 25°C for 10 minutes (annealing step), 48°C for 30 minutes (reverse transcription), and 95°C for 5 minutes (heat killing of the enzyme). The samples can be left at the machine at 4°C, or alternatively, can be stored at - 20°C. Yield of cDNA synthesis can be measured by incorporation of small portion of radioactive dATP (or dCTP). Average efficiency for this protocol is between 60-80%> of conversion of RNA to cDNA.

Protocol of TaqMan real-time quantitative PCR

1 ul of TaqMan RT product in 12.5 ul of lx master Mix (Applied Biosystems Cat#

4304437)containing all necessary reaction components except primers and probes, 0.9 uM forward primer , 0.9 uM reverse primer, 0.2 uM probe. Mix by pipetting up and down. Samples containing GADPH primer pair and probe were also prepared as control. Thermal cycling and detection of the real-time amplification were performed using the ABI PRISM 7900HT Sequuence Detection System. The quantity of target gene is given relative to the GADPH control based on C_t values determined during the exponential phase of PCR.

Primer-probe sets used and their specificities:

Primer 4.1 is unique for hDUB 4.1

Primer 4.2 covers hDUB 4.2, 4.3, 4.5 and 8.1

Primer 8.3 covers hDUB 8.3 and 8.11

Primer 8.5 is unique for hDUB 8.5

Primer 8.6 covers hDUB 8.6, 8.7 and 8.8 Table 1. Expression of hDUBs in PBMC stimulated with LPS (100 ng/ml) and PHA (5 ug/ml) for 7 hours.

Table 2. Expression of hDUBs in PBMC stimulated with LPS (100 ng/ml) for 1.5, 7and 24 hours (Donor 3)

Table 3. Expression of DUBs in PBMC stimulated with LPS (100 ng/ml) and/or PHA (5 ug/ml) for 1.5, 7, 24 hours (donor 4)

There is no increase of expression in T lymphocytes (donor 5) and B lymphocytes (donor 6) when stimulated with anti-CD4/CD28 and anti-CD40/IL-4, respectively. Table 4. Expression of hDUB 4.2, 4.3, 4.5 and 8.1 examined by primer 4.2 in different human organ panel by TaqMan analysis.

Tissue Type Mean B 2 dd Ct Expressi Mean

Adrenal Gland 29.72 20.00 10.08 0.92

Bone marrow 34.02 20.49 13.89 0.07

Brain 26.92 22.73 4.54 42.84

Colon 32.03 19.97 12.42 0.18

Fetal Brain 27.59 24.23 3.71 76.15

Fetal Liver 33.22 22.58 10.99 0.49

Heart 33.09 21.60 11.85 0.27

Kidney 29.93 21.97 8.32 3.13

Lung 32.10 19.31 13.15 0.11

Mammary Gland 30.00 21.74 8.61 2.56

Pancreas 34.83 24.07 11.11 0.45

Placenta 36.60 23.77 13.19 0.00

Prostate 29.14 20.93 8.55 2.66

Salivary Gland 32.11 21.39 11.07 0.46

Skeletal Muscle 28.27 20.44 8.18 3.45

Small Intestine 34.33 21.00 13.69 0.08

Spinal Cord 27.04 21.91 5.47 22.48

Spleen 32.45 19.02 13.78 0.07

Stomach 32.15 21.66 10.84 0.55

Testis 28.57 23.07 5.87 17.16

Thymus 31.01 20.68 10.69 0.61

Thyroid 28.84 20.80 8.39 2.97

Trachea 31.39 19.63 12.11 0.23

Uterus 30.37 21.09 9.64 1.25

PBMC/Control 33.98 18.82 15.52 0.02

PBMC/PMA 33.62 18.81 15.17 0.03

PBMC/PHA 34.20 18.77 15.78 0.02

PBMC/HDM 34.23 17.81 16.77 0.01

A549 Cells 31.98 21.57 10.77 0.57

THP-1 35.48 20.75 15.09 0.00

Ovary 31.84 21.55 10.65 0.62

(+ve) Positive Control 29.61 21.86 8.11 3.62

Table 5. Expression of hDUB 4.2, 4.3, 4.5 and 8.1 examined by primer 4.2 in human immunocytes panel:

Cell Type and stimulation Mean B 2 dd Ct Expression condition Mean

Granulocyte resting 34.18 17.22 17.50 0.005

Granulocyte TNF-.¹ 4/24 hr 32.39 17.16 15.76 0.018

CD19 (tonsillar - CD40L) 28.7 19.92 9.32 1.565 CD19 (tonsillar - LPS) 31.14 20.67 11.00 0.488

FLS-REST 34.67 20.43 14.78 0.036

FLS-IL1 4/24 hr 34.26 ₍ 20.41 14.38 0.047

FLS-TNF-P 4/24 hr 34.91 ^' 20.15 15.31 0.025

Monocyte resting (pool 1.5, 7, 33.63 18.29 15.89 0.017

24 hr)

Monocyte LPS (pool 1.5, 7, 24 34.55 18.03 17.06 0.007 hr)

Monocyte INF-g (pool 1.5, 7, 34.62 17.27 17.88 0.004

24 hr)

Monocyte LPS & IFN- 9 (pool 34.87 17.38 18.03 0.004

1.5, 7, 24 hr)

DCs progenitors (CD 14+) 35.87 19.73 16.67 0.000

DCs immature 35.48 18.18 17.84 0.000

DCs mature 37.46 17.92 20.07 0.000

THO resting 31.11 17.63 14.02 0.060

THO activated 31.29 18.23 13.60 0.081

Thl resting 33.88 18.27 16.15 0.014

Thl CD28/CD3 32.15 19.31 13.38 0.094

Th2 resting 33.94 18.07 16.40 0.012

Th2 CD28/CD3 33.27 18.78 15.02 0.030

BSMC 35.33 21.64 14.22 0.000

BSMC IL-4 + TNF-.¹ 24 hr 36.44 21.52 15.45 0.000

BSMC IL-13 + TNF-.¹ 24 hr 35.94 21.41 15.07 0.000

BSMC IL-4 + IL-13 36.28 22.09 14.73 0.000

NHBE dO 36.63 22.24 14.92 0.000

NHBE IL-4 +TNF-.¹ dO 35.72 21.42 14.83 0.000

NHBE IL-13 +TNF-fdO 36.35 21.37 15.52 0.000

NHBE resting d7 + dl4 34.89 22.41 13.01 0.121

NHBE IL-4 + TNF-.¹ d7 + dl4 38.59 22.02 17.11 0.000

NHBE IL-13 + TNF-f d7 + dl4 37.62 21.93 16.23 0.000

CD8 T cell O hour 30.15 19.52 11.16 0.437

CD8 T cell a-CD3/CD28 4 hour 32.08 19.6 13.01 0.121

CD8 T cell a-CD3/CD28 24 30.94 18.64 12.84 0.137 hour

HMVEC resting 35.09 20.25 15.38 0.000

HMVEC TNF-.¹ + IL-4 24hr 35.91 20.86 15.59 0.000

HMVEC TNF-f 24hr 35.57 21.06 15.05 0.000

HMVEC TNF-J + IL-13 24hr 36.38 20.61 16.31 0.000

Normal synovium pool 34.92 21.16 14.3 0.050

RA synovium pool 33.65 20.88 13.3 0.099

Normal colon 32.5 21.68 11.36 0.381

Colitis Colon 33.17 21.32 12.39 0.187

Crohns colon pooled 32.91 22.06 11.39 0.374

Normal Lung 31.01 20.5 11.05 0.472

COPD Lung 35.09 22.14 13.49 0.000

Positive control 28.4 22.29 6.64 9.992

Cloning ofh DUB4,8s by PCR Following promer set was used to clone 530 amino acid open reading frame portion of single exon hDUB4s and 8s from human genomic DNA:

N-terminal primer: 5'-atggaggacgactcactct-3' (19 mer) C-terminal primer: 5'-ctggcacacaagcaga-3' (19 mer)

Underlined triplet nucleotides in each primer represent translational initiation and termination codon. This primer set can amplify most of hDUB4s and hDUB8s as well as potentially yet to be identified hDUBs that are similar enough to hDUB4s and hDUB8s due to the high homology in nucleotide sequences in this part of the ORF. 1593 base pair fragment was successfully amplified from genomic DNA from two healthy human subjects and cloned into pCR2.1 vector and transformed into TOP10 strain of E coli. Over 300 independent clones with appropriate size insert were obtained and sequences are obtained by ABI automated DNA sequencers.

Deubiquitination Assay

Confirmation that the DUB is a deubiquitinating enzyme may be shown using previously identified deubiquitination assay of ubiquitin— galactosidase fusion proteins, as described previously in the literature. Briefly, a fragment of the DUB, of approximately 1,500 nucleotides, based on the wild-type DUB cDNA (corresponding to amino acids 1 to about 500) and a cDNA containing a missense mutation are generated by PCR and inserted, in frame, into pGEX (Pharmacia), downstream of the glutathione S-transferase (GST) coding element. Ub-Met— gal is expressed from a pACYC184-based plasmid. Plasmids are co- transformed as indicated into MCI 061 Escherichia coli. Plasmid-bearing E. coli MCI 061 cells are lysed and analyzed by immunoblotting with a rabbit anti~gal antiserum (Cappel), a rabbit anti-GST antiserum (Santa Cruz), and the ECL system (Amersham Corp.). in vitro deubiquitinating enzyme activity may be shown from purified hDUB fusion protein using commercial polyubiquitinated protein as substrate.

HDUB4s and hDUB8s are potential inflamatory cytokins specific Immediate-early Genes

mDUB-1 was originally cloned as an IL-3-inducible immediate-early gene. Similarly, mDUB-2 was cloned as an IL-2-inducible immediate-early gene. We examined inducibility as well as cell-type specific expression of these genes using multiple TaqMan analysis from human organ RNA samples and human immunocytes RNA samples. Our data suggest that expression of hDUBs are not apparent in lymphocytes and granulocytes but high in fresh human PBMC from several donor. This strongly suggest that expression may be limited to the monocytes/macrophages and potentially NK cells. hDUB4s and hDUB8s are upregulated in PBMC stimulated with stimuli (LPS and or PHA) that is known to upregulate various inflammatory cytokines such as TNF-alpha, IL-1 beta etc. This increase of expression is almost completely disappeared 20 to 24 hours after stimulation suggesting this is an early gene. The fact that there is only weak expression upregulation at 1.5 hours after stimulation suggests that stimuli by themselves may not upregulate hDUB4s and hDUB8s, but cytokines that are upregulated within couple of hours after stimulation may be responsible for upregulation of the hDUB4s and hDUB8s.

The DUB Subfamily of the ubp Superfamily

From these data we propose that hDUB4s and hDUB8s are members of a discrete subfamily of deubiquitinating enzymes that shows the strongest similarity to mDUB subfamily including mDUBl, mDUB2, and mDUB2A, called the DUB subfamily. DUB subfamily members contain distinct structural features that distinguish them from other ubps. First, DUB subfamily members are comparatively small enzymes of approximately 500-550 amino acids. Second, DUB subfamily members share amino acid similarity not only in the Cys and His domains but also throughout their primary amino acid sequence. For instance, DUB proteins contain a lysine-rich region (Lys domain) and a HV domain near their carboxyl terminus.

The regulatory regions, or promoter regions, of each of the DUBs was analyzed for putative transcription factor binding motifs using TRANSFACFind, a dynamic programming method, see Heinemeyer, T., et al., "Expanding the TRANSFAC database towards an expert system of regulatory molecular mechanisms" Nucleic Acids Res. 27, 318-322, (1999). The Transfac database provides eukaryotic cis- and trans-acting regulatory elements.

Table 6, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 4.1a. The position is indicated by nucleotides.

Table 7, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 4.1b. The position is indicated by nucleotides.

Table 8, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 4.2a. The position is indicated by nucleotides.

Table 9, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 4.2b. The position is indicated by nucleotides.

Table 10, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 4.3. The position is indicated by nucleotides.

Table 11, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 4.4. The position is indicated by nucleotides.

Table 12, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 4.5. The position is indicated by nucleotides.

Table 13, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 8.1. The position is indicated by nucleotides.

Table 14, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 8.2. The position is indicated by nucleotides.

Table 15, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 8.3. The position is indicated by nucleotides.

Table 16, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 8.4. The position is indicated by nucleotides.

Table 17, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 8.5. The position is indicated by nucleotides.

Table 18 putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 8.6. The position is indicated by nucleotides.

Table 19, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 8.7. The position is indicated by nucleotides.

Table 20, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 8.8. The position is indicated by nucleotides.

Table 21, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 8.9. The position is indicated by nucleotides.

Table 22, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 8.10. The position is indicated by nucleotides.

Table 23, putative transcription factor binding motifs within the DUB regulatory or promoter, region of hDUB 8.11. The position is indicated by nucleotides.

References:

1. Baek, K. H., Mondoux, M. A., Jaster, R., Fire-Levin, E., and D'Andrea, A. D. (2001). DUB-2A, a new member of the DUB subfamily of hematopoietic deubiquitinating enzymes, Blood 98, 636-42.

2. Jaster, R., Baek, K. H., and D'Andrea, A. D. (1999). Analysis of cis-acting sequences and trans-acting factors regulating the interleukin-3 response element of the DUB-1 gene, Biochim Biophys Acta 1446, 308-16. 3. Jaster, R., Zhu, Y., Pless, M., Bhattacharya, S., Mathey-Prevot, B., and D'Andrea, A. D.

(1997). JAK2 is required for induction of the murine DUB-1 gene, Mol Cell Biol 17, 3364-72.

4. Migone, T. S., Humbert, M., Rascle, A., Sanden, D., D'Andrea, A., Johnston, J. A., Baek, K. H., Mondoux, M. A., Jaster, R., Fire-Levin, E., et al. (2001). The deubiquitinating enzyme DUB-2 prolongs cytokine-induced signal transducers and activators of transcription activation and suppresses apoptosis following cytokine withdrawal, Blood 98, 1935-41.

5. Zhu, Y., Carroll, M., Papa, F. R, Hochstrasser, M., and D'Andrea, A. D. (1996a). DUB-1, a deubiquitinating enzyme with growth-suppressing activity, Proc Natl Acad Sci U S A 93, 3275-9.

6. Zhu, Y., Lambert, K., Corless, C, Copeland, N. G., Gilbert, D. J., Jenkins, N. A., and D'Andrea, A. D. (1997). DUB-2 is a member of a novel family of cytokine-inducible deubiquitinating enzymes, J Biol Chem 272, 51-7.

7. Zhu, Y., Pless, M., Inhorn, R., Mathey-Prevot, B., and D'Andrea, A. D. (1996b). The murine DUB-1 gene is specifically induced by the betac subunit of interleukin-3 receptor, Mol Cell Biol 16, 4808-17. Nucleotide sequence for hDUB4. la atgaccctgcaacagagcatgcccttctgcattgagcatgcaatcatgaatcacaggcggaggaactgcgagagt gcctacgttagcccaaggcctgacccgacgatcccagggaccctcgacc aactggccccgcctcccgggcccca aacccggactcggcccccccgaagctccggatcctggggcccgcccctggccccgcgtcggaagaccatgggctc gctcctgggccttcctcaaaccctccgcagtccaggcccggcttcctccaggtctccaggcaacgctgcggctcc gcccacgtcatggcgcccgaggagaacgcggggacagaactctggctgcagggtttcgagcgccgcttcctggcg gcgcgc cac gcgctccttcccctggcagagcttagaggcaaagttaagagactcatcagattctgagctgctg cgggatattttgcagaagactgtgaagcatcccgtgtgtgtgaagcacccgccatcagtcaagtatgcccggtgc tttctctcagaactcatcaaaaagggtgcatctgtggtcaccagcagcacgagggctgtccacacggagcctttg gacgagctgtacgaggtgctggcggagactctgatggccaaggagtccacccagggccaccggagctat tgctg ccctcgggaggctcgttcacactttccgagatcacagccatcatctcccatggtactacaggcctggtcacatgg gacgccaccctctaccttgcagaatgggccatcgagaacccagcagccttcactaacaggggtgtcctagagctt ggcagtggcgctggcctcacaggcctggccatctgcaagatgtgtcgcccccaggcatacatcttcagcgactgt cacagccgggtcctcgagcagctccgagggaatgtccttctcaatggcctctcattagaggcagacatcactgcc aacttagacgccccaggagaccacaggagaaaaacaaccacttctgggacgaggacagggcccttgagaaaaggt ggtgtttggctgggccaccgaaaacccctcacccctgccagcacactcagtcccctctctggtggaacagagctc tgcctgtggccctgggtcccagccctgaaacccacaggtccagcggtggccagggacacaggcccacccctgcaa gccagcagaccaaacggcagacacctgaaacaagaagttcacgacgtgctgtattgcccagaagccatcgtgtca ctggtcggggtcctgcggaggctggctgcctgccgggagcacaagcaggctcctgaggtctacctggcctttacc gtccgcaacccagagacgtgccagctgttcaccaccgagctagagatagcgtctttctgcaacctgcggtcccag cagaaaaaccttgtgatccttgttccagtcgacatggaggacgactcactctacttgggaggtgagtggcagttc aaccacttttcaaaactcacatcttctcggccagatgcagcttttgctgaaatccagcgtacttctctccctgag aagtcaccactctcatgtgagacccgtgtcgacctctgtgatgatttggctcctgtggcaagacagcttgctccc agggagaagcctcctctgagtagcaggagacctgctgcggtgggggctgggctccagaatatgggaaatacctgc tacgtgaacgcttccctgcagtgcctgacatacaaaccgccacttgccaactacatgctgttccgggagcactct caaacgtgtcatcg cacaagggctgcatgctctgtactatgcaagctcacatcacaagggccctccacattcct ggccatgtca ccagccctcacaggcattggctgctggcttccatagaggcaagcaggaagatgcccatgaattt ctcatgttcactgtggatgccatgagaaaggcatgccttcccgggcacaagcaggtagatcgtcactctaaggac accaccctcatccaccaaatatttggaggctactggagatctcaaatcaagtgtctccactgccacggcatttca gacacttttgacccttacctggacatcgccctggatatccaggcagctcagagtgtccagcaagctttggaacag ttggtgaagcccgaagaactcaatggagagaatgcctatcattgtggtgtttgtctccagagggcgccggcctcc aagacgttaactttacacaactctgccaaggtcctcatccttgtattgaagagattccccgatgtcacaggcaac aaaattgccaagaatgtgcaatatcctgagtgccttgacatgcagccatacatgtctcagcagaacacaggacct ctcgtctatgtcctctatgctgtgctggtccacgctgggtggagttgtcacaacggacattactcctcttatgtc aaagctcaagaaggccagtggtataaaatggatgatgccgaggtcaccgcctctagcatcacttctgtcctgagt caacaggcctacgtcctcttttacatccagaagagtgaatgggaaagacacagtgagagtgtgtcaagaggcagg gaaccaagagcccttggcgtagaagacacagacaggcgagcaacgcaaggagagctcaagagagaccacccctgc ctccaggcccccgagttggacgagcacttggtggaaagagccactcaggaaagcaccttagaccactggaaattc cttcaagagcaaaacaaaacgaagcctgagttcaacgtcagaagagtcgaaggtacggtgcctcccgacgtactt gtgattcatcaatcaaaatacaagtgtcggatgaagaaccatcatcctgaacagcaaagctccctgctaaacctc tcttcgacgaccccgacagatcaggagtccatgaacactggcacactcgcttccctacgagggaggaccaggaga tccaaagggaagaacaaacacagcaagagggctctgcttgtgtgccagtga hDUB4. la deduced polypeptide sequence

MT QQSMPFCIEHAIMNHRRRNCESAYVSPRPDPTIPGT DLTGPASRAPNPDSAPPKLRI GPAPGPASEDHG APGPSSNPPQSRPGFLQVSRQRCGSAHVMAPEENAGTELWLQGFERRF AARSLRSFP QS EAKLRDSSDSE RDILQKTVKHPVCVKHPPSVKYARCFLSE IKKGASWTSSTRAVHTEPLDE YEV AETLMAKESTQGHRSYLL PSGGSFTLSEITAIISHGTTG VTWDATLYLAE AIENPAAFTNRGVLELGSGAGLTG AICKMCRPQAYIFSDC HSRVLEQ RGNV NG S EADITANLDAPGDHRRKTTTSGTRTGPLRKGGV GHRKPLTPASTLSPLSGGTEL CL PWVPALKPTGPAVARDTGPP QASRPNGRHLKQEVHDVLYCPEAIVSLVGVLRRLAACREHKQAPEVYLAFT VRNPETCQLFTTELEIASFCN RSQQKNLVI VPVDMEDDSLYLGGEWQFNHFSK TSSRPDAAFAEIQRTS PE KSPLSCETRVDLCDD APVARQ APREKPPLSSRRPAAVGAG QN GNTCYVNASLQC TYKPPLANYMLFREHS QTCHRHKGCMLCTMQAHITRALHIPGHVIQPSQALAAGFHRGKQEDAHEF FTVDAMRKACLPGHKQVDRHSKD TTLIHQIFGGYWRSQIKCLHCHG1SDTFDPYLDIALDIQAAQSVQQALEQLVKPEELNGENAYHCGVCLQRAPAS KTLT HNSAKVLI V KRFPDVTGNKIAKNVQYPECLDMQPYMSQQNTGP VYVLYAVLVHAGWSCHNGHYSSYV KAQEGQWYKMDDAEVTASSITSV SQQAYVLFYIQKSE ERHSESVSRGREPRALGVEDTDRRATQGELKRDHPC QAPE DEHLVERATQESTLDHWKFLQEQNKTKPEFNVRRVEGTVPPDVLVIHQSKYKCRMKNHHPEQQSS LNL SSTTPTDQESMNTGTLAS RGRTRRSKGKNKHSKRALLVCQ Nucleotide sequence for hDUB4 . lb atggaggacgactcactctacttgggaggtgagtggcagttcaaccacttttcaaaactcacatcttctcggcca gatgcagcttttgctgaaatccagcgtacttctctccctgagaagtcaccactctcatgtgagacccgtgtcgac ctctgtgatgatttggctcctgtggcaagacagcttgctcccagggagaagcctcctctgagtagcaggagacct gctgcggtgggggctgggctccagaatatgggaaatacctgctacgtgaacgct ccctgcagtgcctgacatac aaaccgccacttgccaactacatgctgttccgggagcactctcaaacgtgtcatcgtcacaagggctgcatgctc tgtactatgcaagctcacatcacaagggccctccacattcctggccatgtcatccagccctcacaggcattggct gctggcttccatagaggcaagcaggaagatgcccatgaatttctcatgttcactgtggatgccatgagaaaggca tgccttcccgggcacaagcaggtagatcg cactctaaggacaccaccctcatccaccaaatatttggaggctac tggagatctcaaatcaagtgtctccactgccacggcatttcagacacttttgacccttacctggacatcgccctg ga a ccaggcagctcagagtgtccagcaagctttggaacagttggtgaagcccgaagaactcaatggagagaat gcctatcattgtggtgtttgtctccagagggcgccggcctccaagacgttaactttacacaactctgccaaggtc ctcatccttgtattgaagagattccccgatgtcacaggcaacaaaattgccaagaatgtgcaatatcctgagtgc cttgacatgcagccatacatgtctcagcagaacacaggacctctcgtctatgtcctctatgctgtgctggtccac gctgggtggagttgtcacaacggacattactcctcttatgtcaaagctcaagaaggccagtggtataaaatggat gatgccgaggtcaccgcctctagcatcacttctgtcctgagtcaacaggcctacgtcctcttttacatccagaag agtgaatgggaaagacacagtgagagtgtgtcaagaggcagggaaccaagagcccttggcgtagaagacacagac aggcgagcaacgcaaggagagctcaagagagaccacccctgcctccaggcccccgagttggacgagcacttggtg gaaagagccactcaggaaagcaccttagaccactggaaattccttcaagagcaaaacaaaacgaagcctgagttc aacgtcagaagagtcgaaggtacggtgcctcccgacgtacttgtgattcatcaatcaaaatacaagtgtcggatg aagaaccatcatcctgaacagcaaagctccctgctaaacctctcttcgacgaccccgacagatcaggagtccatg aacactggcacac cgcttccctacgagggaggaccaggagatccaaagggaagaacaaacacagcaagagggct ctgcttgtgtgccagtga hDUB4. lb deduced polypeptide sequence EDDS Y GGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLSCETRVDLCDD APVARQLAPREKPP SSRRP AAVGAGLQNMGNTCYVNASLQC TYKPPLANYMLFREHSQTCHRHKGCM CTMQAHITRALHIPGHVIQPSQA A AGFHRGKQEDAHEFLMFTVDAMRKAC PGHKQVDRHSKDTTLIHQIFGGYWRSQIKCLHCHGISDTFDPYLDIA DIQAAQSVQQALEQLVKPEELNGENAYHCGVC QRAPASKTLT HNSAKVLILVLKRFPDVTGNKIAKNVQYPEC LDMQPYMSQQNTGP VYV YAVLVHAG SCHNGHYSSYVKAQEGQWYKMDDAEVTASSITSV SQQAYV FYIQK SE ERHSESVSRGREPRALGVEDTDRRATQGE KRDHPC QAPE DEH VERATQESTLDH KF QEQNKTKPEF NVRRVEGTVPPDVLVIHQSKYKCRMKNHHPEQQSSLLN SSTTPTDQESMNTGT AS RGRTRRSKGKNKHSKRA LVCQ

Nucleotide sequence for hDUB4 . a atgggaaatacctgctacgtgaacgcttccttgcagtgcctgacatacacaccgccccttgccaactacatgctg tcccgggagcactctcaaacgtgtcatcgtcacaagggctgcatgctctgtactatgcaagctcacatcacacgg gccctccacaatcctggccacgtcatccagccctcacaggcattggctgctggcttccatagaggcaagcaggaa gatgcccatgaatttctcatgttcactgtggatgccatgaaaaaggcatgccttcccaggcacaagcaggtagat catcactctaaggacaccaccctcatccaccaaatatttggaggctactggagatctcaaatcaagtgtctccac tgccacggcatttcagacacttttgacccttacctggacatcgccctggatatccaggcagctcagagtgtccag caagctttggaacagttggtgaagcccgaagaactcaatggagagaatgcctatcattgtggtgtt gtctccag agggcgccggcctccaagacgttaactttacacacctctgccaaggtcctcatccttgtattgaagagattctcc gatgtcacaggcaacaagattgccaagaatgtgcaatatcctgagtgccttgacatgcagccatacatgtctcag cagaacacaggacctcttgtctatgtcctctatgctgtgctggtccacgctgagtggagttgtcacaacggacat tact ctcttatgtcaaagctcaagaaggccagtggtataaaatggatgatgccgaggtcaccgccgctagcatc acttctgtcctgagtcaacaggcctacgtcctcttttacatccagaagagtgaatgggaaagacatagtgagagt gtgtcaagaggcagggaaccaagagcccttggcgcagaagacacagacaggcgagcaacgcaaggagagctcaag agagaccacccctgcctccaggcccccgagttggacgagcacttggtggaaagagccactcaggaaagcacctta gaccactggaaat ccttcaagagcaaaacaaaacgaagcctgagttcaacgtcagaaaagtcaaaggtacagtg atcaaagttgaccagccccagaggaaagctgcccagggcacaactcagggctccgtagaaccacagaatcttggg cgcaaccctgctcaagcacccaaatgtgcatacgaacagggtctccgtgtgacggaacatgtccactttcggcag cattacaattttggcaccaaatgtgctaactgcaattccaccatacaatgcgtaactggaaatggaggcaacatc gccgatcctgaacgatcgatgcgagaatccaggatatgcacggcttattttggccttttcccactgaaacaaggg ccagtattaaaaatgcagaaaaaccttgtgatcctcgttccagtcgacatggaggacgactcactctacttggga ggtgagtggcagttcaaccacttttcaaaactcacatcttctcggcccgatgcagcttttgctgaaatccagcgg acttctctccctgagaagtcaccactctcatgtgagacccgtgtcgacctctgtgatgatttggctcctgtggca agacagcttgc cccagggagaagcttcctctgagtagcaggagacctgctgcggtgggggctgggctccagaat atgggaaatacctgc acgtgaacgcttccttgcagtgcctgacatacacaacgccccttgccaactacatgctg tcccgggagcactctcaaacgtgtcatcgtcacaagggctgcatgctctgtactatgcaagctcacatcacacgg gccctccacaatcctggccacgtcatccagccctcacaggcattggctgctggcttccatagaggcaagcaggaa gatgcccatgaatttctcatgttcactgtggatgccatgaaaaaggcatgccttcccgggcacaagcaggtagat catcactctaaggacaccaccctcatccaccaaatatttggaggctactggagatctcaaatcaagtgtctccac tgccacggcatttcagacacttttgacccttacctggacatcgccctagatatccaggcagctcagagtgtccag caagctttggaacagttggtgaagcccgaagaactcaatggagagaatgcctatcattctggtgtttgtctccag agggcgccggcctccaagacgttaactttacacacctctgccaaggtcctcatccttgtattgaagagattctcc gatgtcacaggcaacaagattgccaagaatgtgcaatatcctgagtgccttgacatgcagccatacatgtc cag cagaacacaggacctcttgtctatgtcctctatgctgtgctggtccacgctgggtggagttgtcacaacggacat tacttctcttatgtcaaagctcaagaaggccagtggtataaaatggatgatgccgaggtcaccgccgctagcatc acttctgccctgagtcaacaggcctacgtcctcttttacatccagaagagtgaatgggaaagacacagtgagagt gtgtcaagaggcagggaaccaagagcccttggcacagaagacacagacaggcgagcaacgcaaggagagctcaag agagaccacccctgcctccaggcccccgagttggacgagcacttggtggaaagagccactcaggaaagcacctta gaccactggaaattccttcaagagcaaaacaaaacgaagcctgagttcaacgtcagaaaagtcgaaggtaccctg cctcccgacgtacttgtgat catcaatcaaaatacaagtgtgggatgaagaaccatcatcctgaacagcaaagc tccctgctaaacctctcttcgtcgaccccgacacatcaggagtccatgaacactggcacactcgcttccctgcga gggagggccaggagatccaaagggaagaacaaacacagcaagagggctctgcttgtgtgccagtga hDUB4.2a deduced polypeptide sequence GNTCYVNAS QCLTYTPPLANY LSREHSQTCHRHKGCMLCTMQAHITRALHNPGHVIQPSQA AAGFHRGKQE DAHEFLMFTVDAMKKACLPRHKQVDHHSKDTTLIHQIFGGY RSQIKCLHCHGISDTFDPYLDIALDIQAAQSVQ QA EQLVKPEELNGENAYHCGVC QRAPASKTLTLHTSAKV ILVLKRFSDVTGNKIAKNVQYPECLDMQPYMSQ QNTGPLVYV YAVLVHAEWSCHNGHYFSYVKAQEGQWYKMDDAEVTAASITSVLSQQAYV FYIQKSEWERHSES VSRGREPRA GAEDTDRRATQGELKRDHPC QAPELDEHLVERATQESTLDH KFLQEQNKTKPEFNVRKVKGTV IKVDQPQRKAAQGTTQGSVEPQNLGRNPAQAPKCAYEQGLRVTEHVHFRQHYNFGTKCANCNSTIQCVTGNGGNI ADPERSMRESRICTAYFG FPLKQGPVLKMQKNLVILVPVDMEDDS Y GGE QFNHFSKLTSSRPDAAFAEIQR TSLPEKSP SCETRVDLCDDLAPVARQ APREKLP SSRRPAAVGAGLQNMGNTCYVNAS QCLTYTTPLANYML SREHSQTCHRHKGCM CTMQAHITRALHNPGHVIQPSQA AAGFHRGKQEDAHEFL FTVDAMKKAC PGHKQVD HHSKDTT IHQIFGGY RSQIKCLHCHGISDTFDPYLDIA DIQAAQSVQQALEQLVKPEE NGENAYHSGVCLQ RAPASKT TLHTSAKVLILV KRFSDVTGNKIAKNVQYPECLDMQPY SQQNTGPLVYVLYAVLVHAGWSCH GH YFSYVKAQEGQWYKMDDAEVTAASITSALSQQAYV FYIQKSE ERHSESVSRGREPRALGTEDTDRRATQGELK RDHPCLQAPELDEHLVERATQEST DHWKF QEQNKTKPEFNVRKVEGTLPPDV VIHQSKYKCGMKNHHPEQQS S N SSSTPTHQESMNTGTLAS RGRARRSKGKNKHSKRALLVCQ Nucleotide sequence for hDUB4 .2b atggaggacgactcactctacttgggaggtgagtggcagttcaaccacttttcaaaactcacatcttctcggccc gatgcagcttttgctgaaatccagcggacttctctccctgagaagtcaccactctcatgtgagacccgtgtcgac ctctgtgatgatttggctcctgtggcaagacagcttgctcccagggagaagcttcctctgagtagcaggagacct gctgcggtgggggctgggctccagaatatgggaaatacctgctacgtgaacgcttccttgcagtgcctgacatac acaacgccccttgccaactacatgctgtcccgggagcactctcaaacgtgtcatcgtcacaagggctgcatgctc tgtactatgcaagctcacatcacacgggccctccacaatcctggccacgtcatccagccctcacaggcattggct gctggcttccatagaggcaagcaggaagatgcccatgaatttctcatgttcactgtggatgccatgaaaaaggca tgccttcccgggcacaagcaggtagatcatcactctaaggacaccaccctcatccaccaaatatttggaggctac tggagatctcaaatcaagtgtctccactgccacggcatttcagacacttttgacccttacctggacatcgcccta gatatccaggcagctcagagtgtccagcaagctttggaacagttggtgaagcccgaagaactcaatggagagaat gcctatcattctggtgtttgtctccagagggcgccggcctccaagacgttaactttacacacctctgccaaggtc ctcatccttgtattgaagagattctccgatgtcacaggcaacaagattgccaagaatgtgcaatatcctgagtgc cttgacatgcagccatacatgtctcagcagaacacaggacctcttgtctatgtcctctatgctgtgctggtccac gctgggtggagttgtcacaacggacattacttctcttatgtcaaagctcaagaaggccagtggtataaaatggat gatgccgaggtcaccgccgctagcatcacttctgccctgagtcaacaggcctacgtcctcttttacatccagaag agtgaatgggaaagacacagtgagagtgtgtcaagaggcagggaaccaagagcccttggcacagaagacacagac aggcgagcaacgcaaggagagctcaagagagaccacccctgcctccaggcccccgagttggacgagcacttggtg gaaagagccactcaggaaagcaccttagaccactggaaattccttcaagagcaaaacaaaacgaagcctgagttc aacgtcagaaaagtcgaaggtaccctgcctcccgacgtacttgtgattcatcaatcaaaatacaagtgtgggatg aagaaccatcatcctgaacagcaaagctccctgctaaacctctcttcgtcgaccccgacacatcaggagtccatg aacactggcacactcgcttccctgcgagggagggccaggagatccaaagggaagaacaaacacagcaagagggct ctgcttgtgtgccagtga DUB4.2b deduced polypeptide sequence

MEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLSCETRVDLCDDLAPVARQLAPREKLP SSRRP AAVGAGLQNMGNTCYVNASLQCLTYTTP ANYM SREHSQTCHRHKGCMLCTMQAHITRALHNPGHVIQPSQALA AGFHRGKQEDAHEFLMFTVDAMKKAC PGHKQVDHHSKDTTLIHQIFGGY RSQIKCLHCHGISDTFDPYLDIAL DIQAAQSVQQALEQ VKPEELNGENAYHSGVCLQRAPASKT TLHTSAKVLILVLKRFSDVTGNKIAKNVQYPEC DMQPY SQQNTGP VYV YAVLVHAGWSCHNGHYFSYVKAQEGQWYKMDDAEVTAASITSALSQQAYVLFYIQK SEWERHSESVSRGREPRA GTEDTDRRATQGE KRDHPC QAPELDEHLVERATQESTLDH KFLQEQNKTKPEF NVRKVEGTLPPDVLVIHQSKYKCGMKNHHPEQQSS LNLSSSTPTHQESMNTGT AS RGRARRSKGKNKHSKRA LLVCQ

Nucleotide sequence for hDUB 4 . 3 atggaggacgactcactctacttgggaggtgagtggcagttcaaccacttttcaaaactcacatcttctcggccc gatgcagcttttgctgaaatccagcggacttctctccctgagaagtcaccactctcatgtgagacccgtgtcgac ctctgtgatgatttggctcctgtggcaagacagcttgctcccagggagaagcttcctctgagtagcaggagacct gctgcggtgggggctgggctccagaatatgggaaatacctgctacgtgaacgcttccttgcagtgcctgacatac acaccgccccttgccaactacatgctgtcccgggagcactctcaaacgtgtcatcgtcacaagggctgcatgctc tgtacgatgcaagctcacatcacacgggccctccacaatcctggccacgtcatccagccctcacaggcattggct gctggcttccatagaggcaagcaggaagatgcccatgaatttctcatgttcactgtggatgccatgaaaaaggca tgccttcccgggcacaagcaggtaga catcactctaaggacaccaccctcatccaccaaatatttggaggc ac tggagatctcaaatcaagtgtctccactgccacggcatttcagacacttttgacccttacctggacatcgccctg gatatccaggcagctcagagtgtccagcaagctttggaacagttggtgaagcccgaagaactcaatggagagaat gcctatcattgtggtgtttgtctccagagggcgccggcctccaagacgttaactttacacacctctgccaaggtc ctcatccttgtattgaagagattctccgatgtgacaggcaacaagattgccaagaatgtgcaa atcctgagtgc cttgacatgcagccatacatgtctcagcagaacacaggacctcttgtctatgtcctctatgctgtgctggtccac gctgggtggagttgtcacaacggacattacttctcttatgtcaaagctcaagaaggccaatggtataaaatggat gatgccgaggtcaccgccgctagcatcacttctgtcctgagtcaacaggcctacgtcctcttttacatccagaag agtgaatgggaaagacacagtgagagtgtgtcaagaggcagggaaccaagagcccttggcgcagaagacacagac aggcgagcaacgcaaggagagctcaagagagaccacccctgcctccaggcccccgagttggacgagcacttggtg gaaagagccactcaggaaagcaccttagaccgctggaaattccttcaagagcaaaacaaaacgaagcctgagttc aacgtcagaaaagtcgaaggtaccctgcctcccgacgtacttgtgattcatcaatcaaaatacaagtgtgggatg aagaaccatcatcctgaacagcaaagctccctgctaaacctctcttcgtcgaccccgacacatcaggagtccatg aacactggcacactcgcttccctgcgagggagggccaggagatccaaagggaagaacaaacacagcaagagggct ctgcttgtgtgccagtga hDUB4.3 deduced polypeptide sequence EDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKΞPLSCETRVDLCDDLAPVARQLAPREKLPLSSRRP AAVGAG QN GNTCYVNASLQC TYTPPLANY LSREHSQTCHRHKGC CTMQAHITRALHNPGHVIQPSQALA AGFHRGKQEDAHEF MFTVDAMKKAC PGHKQVDHHSKDTTLIHQIFGGY RSQIKC HCHGISDTFDPYLDIA DIQAAQSVQQA EQ VKPEELNGENAYHCGVCLQRAP SKTLTLHTSAKVLI VLKRFSDVTGNKIAKNVQYPEC LDMQPY SQQNTGP VYVLYAVLVHAGWSCHNGHYFSYVKAQEGQWYKMDDAEVTAASITSVLSQQAYVLFYIQK SEWERHSESVSRGREPRALGAEDTDRRATQGELKRDHPC QAPE DEHLVERATQEST DRWKF QEQNKTKPEF NVRKVEGT PPDVLVIHQSKYKCGMKNHHPEQQSSL NLSSSTPTHQES NTGTLASLRGRARRSKGKNKHSKRA LLVCQ

Nucleotide sequence for hDUB 4 . 5 atgcgccagagagctcgtcatttgaagactctctcggaagggatagcgtctttctgcaacctgcggtcccagcag aaaaaccttgtgatccttgttccagtcgacatggaggaagactcactctacttgggaggtgagtggcagttcaac cacttttcaaaactcacatcttctcggcccgatgcagcttttgctgaaatccagcggacttctctccctgagaag tcaccactctcatgtgagacccgtgtcgacctctgtgatgatttggctcctgtggcaagacagct gctcccagg gagaagcttcctctgagtaacaggagacctgctgcggtgggggctgggctccagaatatgggaaatacctgctac gtgaacgcttccttgcagtgcctgacatacacaccgccccttgccaactacatgctgtcccgggagcactctcaa acgtgtcatcgtcacaagggctgcatgctctg acgatgcaagctcacatcacacgggccctccacaatcctggc cacgtcatccagccctcacaggcattggctgctggcttccatagaggcaagcaggaagatgcccatgaatttctc atgttcactgtggatgccatgaaaaaggcatgccttcccgggcacaagcaggtggatcatcactctaaggacacc accctcatccaccaaatatttggaggctactggagatctcaaatcaagtgtctccactgccacggcatttcagac acttttgacccttacctggacatcgccctggatatccaggcagctcagagtgtccagcaagctttggaacagttg gtgaagcccgaagaactcaatggagagaatgcctatcattgtggtgtttgtctccagagggcgccggcctccaag acgttaactttacacacctctgccaaggtcctcatccttgtattgaagagattctccgatgtcacaggcaacaag attgacaagaatgtgcaatatcctgagtgccttgacatgaagctatacatgtctcagacgaactcaggacctctc gtctatgtcctctatgctgtgctggtccacgctgggtggagttgtcacaacggacattacttctcttatgtcaaa gctcaagaaggccagtggtataaaatggatgatgccgaggtcaccgcctctagcatcacttctgtcctgagtcaa caggcctacgtcctcttttacatccagaagagtgaatgggaaagacacagtgagagtgtgtcaagaggcagggaa ccaagagcccttggcgcagaagacacagacaggcgagcaacgcaaggagagctcaagagagaccacccctgcctc caggcccccgagttggacgagcacttggtggaaagagccactcaggaaagcaccttagaccactggaaattcctt caagagcaaaacaaaacgaagcctgagttcaacgtcagaaaagtcgaaggtaccctgcctcccgacgtacttgtg attcatcaatcaaaatacaagtgtgggatgaagaaccatcatcctgaacagcaaagctccctgctaaacctctct tcgacgaccccgacacatcaggagtccatgaacactggcacactcgcttccctgcgagggagggccaggagatcc aaagggaagaacaaacacagcaagagggctctgcttgtgtgccagtggtctcagtggaagtaccgacccaca hDUB4.5 deduced polypeptide sequence

MRQRARHLKTLSEGIASFCNLRSQQKNLVILVPVD EEDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEK SPLSCETRVDLCDDLAPVARQLAPREKLPLSNRRPAAVGAGLQNMGNTCYVNASLQCLTYTPPLANY LSREHSQ TCHRHKGCMLCTMQAHITRALHNPGHVIQPSQALAAGFHRGKQEDAHEFLMFTVDAMKKACLPGHKQVDHHSKDT TLIHQIFGGYWRSQIKCLHCHGISDTFDPYLDIALDIQAAQSVQQALEQLVKPEELNGENAYHCGVCLQRAPASK TLTLHTSAKVLILVLKRFSDVTGNKIDKNVQYPECLDMKLYMSQTNSGPLVYVLYAVLVHAGWSCHNGHYFSYVK AQEGQWYKMDDAEVTASSITSVLSQQAYVLFYIQKSE ERHSESVSRGREPRALGAEDTDRRATQGELKRDHPCL QAPELDEHLVERATQESTLDH KFLQEQNKTKPEFNVRKVEGTLPPDVLVIHQSKYKCGMKNHHPEQQSSLLNLS STTPTHQES NTGTLASLRGRARRSKGKNKHSKRALLVCQWSQWKYRPT Nucleotide sequence for hDUB4 . 6 atggaggacg actcactcta cttgggaggt gagtggcagt tcaaccactt ttcaaaactc acatcttctc ggcccgatgc agcttttgct gaaatccagc ggacttctct ccctgagaag tcaccactct catgtgagac ccgtgtcgac ctctgtgatg atttggctcc tgtggcaaga cagcttgctc ccagggagaa gcttcctctg agtagcagga gacctgctgc ggtgggggct gggctccaga atatgggaaa tacctgctac gtgaacgctt ccttgcagtg cctgacatac acaccgcccc ttgccaacta catgctgtcc cgggagcact ctcaaacgtg tcatcgtcac aagggctgta tgctctgtac gatgcaagct cacatcacac gggccctcca caatcctggc cacgtcatcc agccctcaca ggcattggct gctggcttcc atagaggcaa gcaggaagat gcccatgaat ttctcatgtt cactgtggat gccatgaaaa aggcatgcct tcccgggcac aagcaggtgg atcatcactc taaggacacc accctcatcc accaaatatt tggaggctac tggagatctc aaatcaagtg tctccactgc cacggcattt cagacacttt tgacccttac ctggacatcg ccctggatat ccaggcagct cagagtgtcc agcaagcttt ggaacagttg gtgaagcccg aagaactcaa tggagagaat gcctatcatt gtggtgtttg tctccagagg gcgccggcct ccaagacgtt aactttacac acctctgcca aggtcctcat ccttgtattg aagagattct ccgatgtcac aggcaacaag attgccaaga atgtgcaata tcctgagtgc cttgacatgc agccatacat gtctcagacg aacacaggac ctctcgtcta tgtcctctat gctgtgctgg tccacgctgg gtggagttgt cacaacggac attacttctc ttatgtcaaa gctcaagaag gccagtggta taaaatggat gatgccgagg tcaccgcctc tagcatcact tctgtcctga gtcaacaggc ctacgtcctc ttttacatcc agaagagtga atgggaaaga cacagtgaga gtgtgtcaag aggcagggaa ccaagagccc ttggcgcaga agacacagac aggcgagcaa cgcaaggaga gctcaagaga gaccacccct gcctccaggc ccccgagttg gacgagcact tggtggaaag agccactcag gaaagcacct tagaccactg gaaattcctt caagagcaaa acaaaacgaa gcctgagttc aacgtcagaa aagtcgaagg taccctgcct cccgacgtac ttgtgattca tcaatcaaaa tacaagtgtg ggatgaagaa ccatcatcct gaacagcaaa gctccctgct aaacctctct tcgacgaccc cgacacatca ggagtccatg aacactggca cactcgcttc cctgcgaggg agggccagga gatccaaagg gaagaacaaa cacagcaaga gggctctgct tgtgtgccag tga hDUB4.6 deduced polypeptide sequence MEDDSLYLGG EWQFNHFSKL TSSRPDAAFA EIQRTSLPEK SPLSCETRVD LCDDLAPVAR QLAPREKLPL SSRRPAAVGA GLQNMGNTCY VNASLQCLTY TPPLANYMLS REHSQTCHRH KGCMLCTMQA HITRALHNPG HVIQPSQALA AGFHRGKQED AHEFLMFTVD AMKKACLPGH KQVDHHSKDT TLIHQIFGGY WRSQIKCLHC HGISDTFDPY LDIALDIQAA QSVQQALEQL VKPEELNGEN AYHCGVCLQR AP SKTLTLH TSAKVLILVL KRFSDVTGNK IAKNVQYPEC LDMQPYMSQT NTGPLVYVLY AVLVHAGWSC HNGHYFSYVK AQEGQ YK D DAEVTASSIT SVLSQQAYVL FYIQKSEWER HSESVSRGRE PRALGAEDTD RRATQGELKR DHPCLQAPEL DEHLVERATQ ESTLDH KFL QEQNKTKPEF NVRKVEGTLP PDVLVIHQSK YKCGMKNHHP EQQSSLLNLS STTPTHQES NTGTLASLRG RARRSKGKNK HSKRALLVCQ

Nucleotide sequence for hDUB 4 .7 atggaggacg actcactcta cttgggtggt gagtggcagt tcaaccactt ttcaaaactc acatcttctc ggcccgatgc agcttttgct gaaatccagc ggacttctct ccctgagaag tcaccactct catgtgagac ccgtgtcgac ctctgtgatg atttggctcc tgtggcaaga cagcttgctc ccagggagaa gcttcctctg agtagcagga gacctgctgc ggtgggggct gggctccaga atatgggaaa tacctgctac gtgaacgctt ccttgcagtg cctgacatac acaccgcccc ttgccaacta catgctgtcc cgggagcact ctcaaacgtg tcatcgtcac aagggctgca tgctctgtac tatgcaagct cacatcacac gggccctcca caatcctggc cacgtcatcc agccctcaca ggcattggct gctggcttcc atagaggcaa gcaggaagat gcccatgaat ttctcatgtt cactgtggat gccatgaaaa aggcatgcct tcccgggcac aagcaggtag atcatcactc taaggacacc accctcatcc accaaatatt tggaggctac tggagatctc aaatcaactg tctccactgc cacggcattt cagacacttt tgacccttac ctggacatcg ccctggatat ccaggcagct cagagtgtcc agcaagcttt ggaacagttg gtgaagcccg aagaactcaa tggagagaat gcctatcatt gtggtgtttg tctccagagg gcgccggcct ccaagacgtt aactttacac acctctgcca aggtcctcat ccttgtattg aagagattct ccgatgtcac aggcaacaag attgccaaga atgtgcaata tcctgagtgc cttgacatgc agccatacat gtctcagcag aacacaggac ctcttgtcta tgtcctctat gctgtgctgg tccacgctgg gtggagttgt cacaacggac attacttctc ttatgtcaaa gctcaagaag gccagtggta taaaatggat gatgccgagg tcaccgccgc tagcatcact tctgtcctga gtcaacaggc ctacgtcctc ttttacatcc agaagagtga atgggaaaga cacagtgaga gtgtgtcaag aggcagggaa ccaagagccc ttggcgcaga agacacagac aggcgagcaa cgcaaggaga gctcaagaga gaccacccct gcctccaggc ccccgagttg gacgagcact tggtggaaag agccactcag gaaagcacct tagaccactg gaaattcctt caagagcaaa acaaaacgaa gcctgagttc aacgtcagaa aagtcgaagg taccctgcct cccgacgtac ttgtgattca tcaatcaaaa tacaagtgtg ggatgaagaa ccatcatcct gaacagcaaa gctccctgct aaacctctct tcgtcgaccc cgacacatca ggaggccatg aacactggca cactcgcttc cctgcgaggg aggaccagga gatccaaagg gaagaacaaa cacagcaaga gggctctgct tgtgtgccag tga hDUB4.7 deduced polypeptide sequence

MEDDSLYLGG EWQFNHFSKL TSSRPDAAFA EIQRTSLPEK SPLSCETRVD LCDDLAPVAR QLAPREKLPL SSRRPAAVGA GLQNMGNTCY VNASLQCLTY TPPLANYMLS REHSQTCHRH KGCMLCTMQA HITRALHNPG HVIQPSQALA AGFHRGKQED AHEFLMFTVD AMKKACLPGH KQVDHHSKDT TLIHQIFGGY WRSQINCLHC HGISDTFDPY LDIALDIQAA QSVQQALEQL VKPEELNGEN AYHCGVCLQR APASKTLTLH TSAKVLILVL KRFSDVTGNK IAKNVQYPEC LDMQPYMSQQ NTGPLVYVLY AVLVHAGWSC HNGHYFSYVK AQEGQWYKMD DAEVTAASIT SVLSQQAYVL FYIQKSEWER HSESVSRGRE PRALGAEDTD RRATQGELKR DHPCLQAPEL DEHLVERATQ ESTLDHWKFL QEQNKTKPEF NVRKVEGTLP PDVLVIHQSK YKCGMKNHHP EQQSSLLNLS SSTPTHQEAM NTGTLASLRG RTRRSKGKNK HSKRALLVCQ

Nucleotide sequence for hDUB4. 8 atgcgccaga gagctcgtca tttgaagact ctctcggaag ggatagcgtc ttgctgcaaa ctgcggtccc agcagaaaaa ccttgtgatc cttgttccag tcgacatgga ggacgactca ctctacttgg gaggtgagtg gcagttcaac cacttttcaa aactcacatc ttctcggccc gatgcagctt ttgctgaaat ccagcggact tctctccctg agaagtcacc actctcatgt gagacccgtg tcgacctctg tgatgatttg gctcctgtgg caagacagct tgctcccagg gagaagcttc ctctgagtag caggagacct gctgcggtgg gggctgggct ccagaatatg ggaaatacct gctacgtgaa cgcttccttg cagtgcctga catacacacc gccccttgcc aactacatgc tgtcccggga gcactctcaa acgtgtcatc gtcacaaggg ctgcatgctc tgtacgatgc aagctcacat cacacgggcc ctccacaatc ctggccacgt catccagccc tcacaggcat tggctgctgg cttccataga ggcaagcagg aagatgccca tgaatttctc atgttcactg tggatgccat gaaaaaggca tgccttcccg ggcacaagca ggtagatcat cactctaagg acaccaccct catccaccaa atatttggag gctactggag atctcaaatc aagtgtctcc actgccacgg catttcagac acttttgacc cttacctgga catcgccctg gatatccagg cagctcagag tgtccagcaa gctttggaac agttggtgaa gcccgaagaa ctcaatggag agaatgccta tcattgtggt gtttgtctcc agagggcgcc ggcctccaag acgttaactt tacacacctc tgccaaggtc ctcatccttg tattgaagag attctccgat gtgacaggca acaagattgc caagaatgtg caatatcctg agtgccttga catgcagcca tacatgtctc agcagaacac aggacctctt gtctatgtcc tctatgctgt gctggtccac gctgggtgga gttgtcacaa cggacattac ttctcttatg tcaaagctca agaaggccaa tggtataaaa tggatgatgc cgaggtcacc gccgctagca tcacttctgt cctgagtcaa caggcctacg tcctctttta catccagaag agtgaatggg aaagacacag tgagagtgtg tcaagaggca gggaaccaag agcccttggc gcagaagaca cagacaggcg agcaacgcaa ggagagctca agagagacca cccctgcctc caggcccccg agttggacga gcacttggtg gaaagagcca ctcaggaaag caccttagac cactggaaat tccttcaaga gcaaaacaaa acgaagcctg agttcaacgt cagaaaagtc gaaggtaccc tgcctcccga cgtacttgtg attcatcaat caaaatacaa gtgtgggatg aagaaccatc atcctgaaca gcaaagctcc ctgctaaacc tctcttcgtc gaccccgaca catcaggagt ccatgaacac tggcacactc gcttccctgc gagggagggc caggagatcc aaagggaaga acaaacacag caagagggct ctgcttgtgt gccagtga hDUB4.8 deduced polypeptide sequence

MRQRARHLKT LSEGIASCCK LRSQQKNLVI LVPVDMEDDS LYLGGEWQFN HFSKLTSSRP DAAFAEIQRT SLPEKSPLSC ETRVDLCDDL APVARQLAPR EKLPLSSRRP AAVGAGLQNM GNTCYVNASL QCLTYTPPLA NYMLSREHSQ TCHRHKGCML CTMQAHITRA LHNPGHVIQP SQALAAGFHR GKQEDAHEFL MFTVDAMKKA CLPGHKQVDH HSKDTTLIHQ IFGGYWRSQI KCLHCHGISD TFDPYLDIAL DIQAAQSVQQ ALEQLVKPEE LNGENAYHCG VCLQRAPASK TLTLHTSAKV LILVLKRFSD VTGNKIAKNV QYPECLDMQP YMSQQNTGPL VYVLYAVLVH AGWSCHNGHY FSYVKAQEGQ WYKMDDAEVT AASITSVLSQ QAYVLFYIQK SEWERHSESV SRGREPRALG AEDTDRRATQ GELKRDHPCL QAPELDEHLV ERATQESTLD HWKFLQEQNK TKPEFNVRKV EGTLPPDVLV IHQSKYKCGM KNHHPEQQSS LLNLSSSTPT HQESMNTGTL ASLRGRARRS KGKNKHSKRA LLVCQ

Nucleotide sequence for hDUB 4 . 10 atgtgcatac gaacagggtc tccgtgtgac gtgtgtgaaa actacagtgt gatgagcatg actggcagac agcttatcga ttgggctccc ctcaaaatcg gttatgagca ttcaagcaca ccgatgccca gggaacatgt ccactttcgg cagcattaca attttggcac caaatgtgct aactgcaatt ccaccataca atgcgtaact ggaaatggag gcaacatcgc cgatcctgaa cgatcgatgc gagaatccag gatatgcacg gcttattttg gccttttccc actgaaacaa gggccagtat taaaaatggt aatttcactc ggacagagaa tcaataggct caacgtggaa aggttatcgc tggaagggaa gaaaatacgc tgtgctaaat actatacttc attgactatt ctcaggtcag aaagcgcact ttcgacttct tgtccttccg tcgctgagag gatgatggca gctgccaaaa ggatagcgtc tttctgcaac ctgcggtccc agcagaaaaa ccttgtgatc ctcgttccag tcgacatgga ggacgactca ctctacttgg gaggtgagtg gcagttcaac cacttttcaa aactcacatc ttctcggccc gatgcagctt ttgctgaaat ccagcggact tctctccctg agaagtcacc actctcatgt gagacccgtg tcgacctctg tgatgatttg gctcctgtgg caagacagct tgctcccagg gagaagcttc ctctgagtag caggagacct gctgcggtgg gggctgggct ccagaatatg ggaaatacct gctacgtgaa cgcttccttg cagtgcctga catacacaac gccccttgcc aactacatgc tgtcccggga gcactctcaa acgtgtcatc gtcacaaggg ctgcatgctc tgtactatgc aagctcacat cacacgggcc ctccacaatc ctggccacgt catccagccc tcacaggcat tggctgctgg cttccataga ggcaagcagg aagatgccca tgaatttctc atgttcactg tggatgccat gaaaaaggca tgccttcccg ggcacaagca ggtagatcat cactctaagg acaccaccct catccaccaa atatttggag gctactggag atctcaaatc aagtgtctcc actgccacgg catttcagac acttttgacc cttacctgga catcgcccta gatatccagg cagctcagag tgtccagcaa gctttggaac agttggtgaa gcccgaagaa ctcaatggag agaatgccta tcattctggt gtttgtctcc agagggcgcc ggcctccaag acgttaactt tacacacctc tgccaaggtc ctcatccttg tattgaagag attctccgat gtcacaggca acaagattgc caagaatgtg caatatcctg agtgccttga catgcagcca tacatgtctc agcagaacac aggacctctt gtctatgtcc tctatgctgt gctggtccac gctgggtgga gttgtcacaa cggacattac ttctcttatg tcaaagctca agaaggccag tggtataaaa tggatgatgc cgaggtcacc gccgctagca tcacttctgc cctgagtcaa caggcctacg tcctctttta catccagaag agtgaatggg aaagacacag tgagagtgtg tcaagaggca gggaaccaag agcccttggc acagaagaca cagacaggcg agcaacgcaa ggagagctca agagagacca cccctgcctc caggcccccg agttggacga gcacttggtg gaaagagcca ctcaggaaag caccttagac cactggaaat tccttcaaga gcaaaacaaa acgaagcctg agttcaacgt cagaaaagtc gaaggtaccc tgcctcccga cgtacttgtg attcatcaat caaaatacaa gtgtgggatg aagaaccatc atcctgaaca gcaaagctcc ctgctaaacc tctcttcgtc gaccccgaca catcaggagt ccatgaacac tggcacactc gcttccctgc gagggagggc caggagatcc aaagggaaga acaaacacag caagagggct ctgcttgtgt gccagtga

hDUB4.10 deduced polypeptide sequence

MCIRTGSPCD VCENYSVMSM TGRQLIDWAP LKIGYEHSST PMPREHVHFR QHYNFGTKCA NCNSTIQCVT GNGGNIADPE RSMRESRICT AYFGLFPLKQ GPVLKMVISL GQRINRLNVE RLSLEGKKIR CAKYYTSLTI LRSESALSTS CPSVAERMMA AAKRIASFCN LRSQQKNLVI LVPVDMEDDS LYLGGEWQFN HFSKLTSSRP DAAFAEIQRT SLPEKSPLSC ETRVDLCDDL APVARQLAPR EKLPLSSRRP AAVGAGLQNM GNTCYVNASL QCLTYTTPLA NYMLSREHSQ TCHRHKGCML CTMQAHITRA LHNPGHVIQP SQALAAGFHR GKQEDAHEFL MFTVDAMKKA CLPGHKQVDH HSKDTTLIHQ IFGGYWRSQI KCLHCHGISD TFDPYLDIAL DIQAAQSVQQ ALEQLVKPEE LNGENAYHSG VCLQRAPASK TLTLHTSAKV LILVLKRFSD VTGNKIAKNV QYPECLDMQP YMSQQNTGPL VYVLYAVLVH AGWSCHNGHY FSYVKAQEGQ WYKMDDAEVT AASITSALSQ QAYVLFYIQK SEWERHSESV SRGREPRALG TEDTDRRATQ GELKRDHPCL QAPELDEHLV ERATQESTLD HWKFLQEQNK TKPEFNVRKV EGTLPPDVLV IHQSKYKCGM KNHHPEQQSS LLNLSSSTPT HQESMNTGTL ASLRGRARRS KGKNKHSKRA LLVCQ

Nucleotide sequence for hDUB4 .11 atgtgcatac gaacagggtc tccgtgtgac gtgtgtgaaa actacagtgt gatgagcatg actggcagac agcttatcga ttgggctccc ctcaaaatcg gttatgagca ttcaagcaca ccgatgccca ggacacttta catccggcac aggaagcctt ctgatggagc acacctggcc catgaaaaga caagggaaag aaacggggcc aaagggaaga aaatacgctg tgctaaatac tatacttcat tgactattct caggtcagaa agcgcacttt cgtcttcttg tccttccgtc gcggagagga tgatggcagc tgccaaaatc gacatggagg acgactcact ctacttggga ggtgagtggc agttcaacca cttttcaaaa ctcacatctt ctcggccaga tgcagctttt gctgaaatcc agcggacttc tctccctgag aagtcaccac tctcatatga tttggctcct gtggcaagac agcttgctcc cagggagaag cttcctctga gtagcaggag acctgctgcg gtgggggctg ggctccagaa tatgggaaat acctgctacg tgaacgcttc cttgcagtgc ctgacataca caccgcccct tgccaactac atgctgtccc gggagcactc tcaaacgtgt catcgtcaca agggctgcat gctctgtact atgcaagctc acatcacacg ggccctccac aatcctggcc acgtcatcca gccctcacag gcattggctg ctggcttcca tagaggcaag caggaagatg cccatgaatt tctcatgttc actgtggatg ccatgaaaaa ggcatgcctt cccaggcaca agcaggtaga tcatcactct aaggacacca ccctcatcca ccaaatattt ggaggctact ggagatctca aatcaagtgt ctccactgcc acggcatttc agacactttt gacccttacc tggacatcgc cctggatatc caggcagctc agagtgtcca gcaagctttg gaacagttgg tgaagcccga agaactcaat ggagagaatg cctatcattg tggtgtttgt ctccagaggg cgccggcctc caagacgtta actttacaca cctctgccaa ggtcctcatc cttgtattga agagattctc cgatgtcaca ggcaacaaga ttgccaagaa tgtgcaatat cctgagtgcc ttgacatgca gccatacatg tctcagcaga acacaggacc tcttgtctat gtcctctatg ctgtgctggt ccacgctgag tggagttgtc acaacggaca ttacttctct tatgtcaaag ctcaagaagg ccagtggtat aaaatggatg atgccgaggt caccgccgct agcatcactt ctgtcctgag tcaacaggcc tacgtcctct tttacatcca gaagagtgaa tgggaaagac atagtgagag tgtgtcaaga ggcagggaac caagagccct tggcgcagaa gacacagaca ggcgagcaac gcaaggagag ctcaagagag accacccctg cctccaggcc cccgagttgg acgagcactt ggtggaaaga gccactcagg aaagcacctt agaccactgg aaattccttc aagagcaaaa caaaacgaag cctgagttca acgtcagaaa agtcaaaggt accctgcctc ccgacgtact tgtgattcat caatcaaaat acaagtgtgg gatgaagaac catcatcctg aacagcaaag ctccctgcta aacctctctt cgtcgacccc gacacatcag gagtccatga acactggcac actcgcttcc ctgcgaggga gggccaggag atccaaaggg aagaacaaac acagcaagag ggctctgctt gtgtgccagt ga hDUB4.11 deduced polypeptide sequence

MCIRTGSPCD VCENYSVMSM TGRQLIDWAP LKIGYEHSST PMPRTLYIRH RKPSDGAHLA HEKTRERNGA KGKKIRCAKY YTSLTILRSE SALSSSCPSV AERMMAAAKI DMEDDSLYLG GEWQFNHFSK LTSSRPDAAF AEIQRTSLPE KSPLSYDLAP VARQLAPREK LPLSSRRPAA VGAGLQNMGN TCYVNASLQC LTYTPPLANY MLSREHSQTC HRHKGCMLCT MQAHITRALH NPGHVIQPSQ ALAAGFHRGK QEDAHEFLMF TVDAMKKACL PRHKQVDHHS KDTTLIHQIF GGYWRSQIKC LHCHGISDTF DPYLDIALDI QAAQSVQQAL EQLVKPEELN GENAYHCGVC LQRAPASKTL TLHTSAKVLI LVLKRFSDVT GNKIAKNVQY PECLDMQPYM SQQNTGPLVY VLYAVLVHAE WSCHNGHYFS YVKAQEGQWY KMDDAEVTAA SITSVLSQQA YVLFYIQKSE WERHSESVSR GREPRALGAE DTDRRATQGE LKRDHPCLQA PELDEHLVER ATQESTLDHW KFLQEQNKTK PEFNVRKVKG TLPPDVLVIH QSKYKCGMKN HHPEQQSSLL NLSSSTPTHQ ESMNTGTLAS LRGRARRSKG KNKHSKRALL VCQ

Nucleotide sequence for hDUB 8 .1 atgggggacgactcactctacttgggaggtgagtggcagttcaaccacttttcaaaactcacatcttctcggcca gatgcagcttttgctgaaatccagcggacttctctccctgagaagtcaccactctcatctgagacccgtgtcgac ctctgtgatgatttggctcctgtggcaagacagctcgctcccagggagaagcttcctctgagtagcaggagacct gctgcggtgggggctgggctccagaatatgggaaatacctgctacgagaacgcttccctgcagtgcctgacatac acactgccccttgccaactacatgctgtcccgggagcactctcaaacatgtcagcgtcccaagtgctgcatgctc tgtactatgcaagctcacatcacatgggccctccacagtcctggccatgtcatccagccctcacaggcattggct gctggcttccatagaggcaagcaggaagatgtccatgaatttctcatgttcactgtggatgccatgaaaaaggca tgccttcccggccacaagcaggtagatcatcactgcaaggacaccaccctcatccaccaaatatttggaggctgc tggagatctcaaatcaagtgtctccactgccacgggatttcagacacttttgacccttacctggacatcgccctg gatatccaggcagctcagagtgtcaagcaagctttggaacagttggtgaagcccgaagaactcaatggagagaat gcctatcattgcggtctttgtctccagagggcgccggcctccaacacgttaactttacacacttctgccaaggtc ctcatccttgtcttgaagagattctccgatgtcgcaggcaacaaacttgccaagaatgtgcaatatcctgagtgc cttgacatgcagccatacatgtctcagcagaacacaggacctcttgtctatgtcctctatgctgtgctggtccac gctgggtggagttgtcacgacggacattacttctcctatgtcaaagctcaagaagtccagtggtataaaatggat gatgccgaggtcactgtctgtagcatcatttctgtcctgagtcaacaggcctatgtcctcttttacatccagaag agtgaatgggaaagacacagtgagagtgtgtcaagaggcagggaaccaagagccctcggcgctgaagacacagac aggcgagcaaagcaaggagagctcaagagagaccacccctgcctccaggcacccgagttggacgagcacttggtg gaaagagccactcaggaaagcaccttagaccactggaaattcctgcaagagcaaaacaaaacgaagcctgagttc aacgtcggaaaagtcgaaggtaccctgcctcccaacgcacttgtgattcatcaatcaaaatacaagtgtgggatg aaaaaccatcatcctgaacagcaaagctccctgctaaacctctcttcgacgacccggacagatcaggagtccatg aacactggcacactcgcttctctgcaagggaggaccaggagagccaaagggaagaacaaacacagcaagagggct ctgcttgtgtgccagtga hDUBδ.l deduced polypeptide sequence MGDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLSSETRVDLCDDLAPVARQLAPREKLPLSSRRP AAVGAGLQNMGNTCYENASLQCLTYTLPLANYMLSREHSQTCQRPKCCMLCTMQAHITWALHSPGHVIQPSQALA AGFHRGKQEDVHEFLMFTVDAMKKACLPGHKQVDHHCKDTTLIHQIFGGCWRSQIKCLHCHGISDTFDPYLDIAL DIQAAQSVKQALEQLVKPEELNGENAYHCGLCLQRAPASNTLTLHTSAKVLILVLKRFSDVAGNKLAKNVQYPEC LDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHDGHYFSYVKAQEVQWYKMDDAEVTVCSIISVLSQQAYVLFYIQK SEWERHSESVSRGREPRALGAEDTDRRAKQGELKRDHPCLQAPELDEHLVERATQESTLDHWKFLQEQNKTKPEF NVGKVEGTLPPNALVIHQSKYKCGMKNHHPEQQSSLLNLSSTTRTDQESMNTGTLASLQGRTRRAKGKNKHSKRA LLVCQ

Nucleotide sequence for HDUB8.3 Atggaggacgactcactctacttgggaggtgagtggcagttcaaccacttttcaaaactcacatcttctcggcca gatgcagcctttgctgaaatccagcGgacttctctccctgagaagtcacaactctcaactgagacccgcgtcgac ttctgcgatgatttggcgcctgtggcaagacagcttgctcccagggagaaGcttcctctgagtagcaggagacct gctgcggtgggggctgggctccagaatatgggaaatacctgctacgtgaacgcttcccagcagtgtctgacatac Acaccgccccttgccaactacatgctgtcccgggagcactctcaaacatgtcatcgtcacaagtgctgcatgctc tgtaccatggaagctcacatcacatGgcccctccacattcctggccatgtcatccagccctcacaggcattggct gctggcttccatagaggcaagcaggaagctgcccttgaatttctcatgttCactgtggatgccatgaaaaaggca tgccttcccgggcacaagcaggtagatcatcactccaaggacaccaccctca ccaccaaatatttggagggtac Tggagatctcaaatcaagtgtctccactgccacggcatttcagacacttttggcccttacctggacatcgccctg gatatccaggaagctcagagtgtcaAgcaagctttggaacagttggtgaagcccgaagaactcaatggagagaat gcctatcattgtggcaacaaaattgccaagaatgtgcaatatcctgagtgCcttgacatgcagccatacatgtct cagcagaacacaggacctcttgtctatgtcctctatgctgtgctggtccacgccgggtggagttgtcacaacgga Cattacttctcttatgtcaaagttcaagaaggccagtggtataaaatggatgatgccgaggtcactgcctctggc atcacctctgtcctgagtcaacaggCctatgtcctcttttacatccacaagagtgaatgggaaagacacagtgag agtgtgtcaagaggcagggaaccaagagccctcggcgctgaagacacagaCaggcgagcaacgcaaggagagctc aagagagactacccctgcctccaggtacccgagttggacgagcacttggtggaaagagccactcaggaaagcacc Ttagaccactggaaattcctccaagagcaaaacaaaacgaagcctgagttcaacgtcagaaaacttgaaggtacc ctgcctcccaacgtacttgtgattcAtcaatcaaaatacaagtgtgggatgaaaaaccatcatcctgaacagcaa agctccctgctaaacctctcttcgacgaacccgacagatcaggagtccatGaacactggcacactcgcttctctg caagggaggaccaggagagccaaagggaagaacaaacactgcaagagggctctgcttgtgtgccagtga

HDUB8.3 deduced polypeptide sequence MEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSQLSTETRVDFCDDLAPVARQLAPREKLPLSSRRP AAVGAGLQNMGNTCYVNASQQCLTYTPPLANYMLSREHSQTCHRHKCCMLCTMEAHITWPLHIPGHVIQPSQALA AGFHRGKQEAALEFLMFTVDAMKKACLPGHKQVDHHSKDTTLIHQIFGGYWRSQIKCLHCHGISDTFGPYLDIAL DIQEAQSVKQALEQLVKPEELNGENAYHCGNKIAKNVQYPECLDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHNG HYFSYVKVQEGQWYKMDDAEVTASGITSVLSQQAYVLFYIHKSEWERHSESVSRGREPRALGAEDTDRRATQGEL KRDYPCLQVPELDEHLVERATQESTLDHWKFLQEQNKTKPEFNVRKLEGTLPPNVLVIHQSKYKCGMKNHHPEQQ SSLLNLSSTNPTDQESMNTGTLASLQGRTRRAKGKNKHCKRALLVCQ

Nucleotide sequence for HDUB8.5

Atggaggacgactcactctacttgggaggtgagtggcagttcaaccacttttcaaaactcacatcttctcggcca gatgcagcttttgctgaaatccagcGgacttctctccctgagaagtcaccactctcatctgaggcccgtgtcgac ctctgtgatgatttggctcctgtggcaagacagcttgctcccaggaagaaGcttcctctgagtagcaggagacct gctgcggtgggggctgggctccagaatatgggaaatacctgctacgagaacgcttccctgcagtgcctgacatac Acaccgccccttgccaactacatgctgtcccgggagcactctcaaacatgtcagcgtcccaagtgctgcatgctc tgtactatgcaagctcacatcacatGggccctccacagtcctggtcatgtcatccagccctcacaggcattggct gctggcttccatagaggcaagcaggaagatgcccatgaatttctcatgttCactgtggatgccatgaaaaaggca tgccttcccggccacaagcaggtagatcatcactctaaggacaccaccctcatccaccaaatatttggaggctgc Tggagatctcaaatcaagtgtctccactgccacgggatttcagacacttttgacccttacctggacatcgccctg gatatccaggcagctcagagtgtcaAgcaagctttggaacagttggtgaagcccgaagaactcaatggagagaat gcctatcattgcggtctttgtcttcagagggcgccagtctccaagacgttAactttacacacttttgccaaggaa cgcatacttgaaacgcagagaccatgggtggtcacacgccacaaactagccaagagtgtgcaatatgctgagagc Cttgacatgcagccatacatgtctcagcagaacacaggacctcttgtctatgtcctctatgctgtgctggtccac gctgggtggagttgtcacgatggacAttacttctcttatgtcaaagctcaagaaggccagtggtataaaatggat gatgccaaggtcactgcctgtagcatcacttctgtcctgagtcaacaggcCtatgtcctcttttacatccagaag agtgaatgggaaagacacagtgagagtgtgtcaagaggcagggaaccaagagccctcggcgctgaagacacagac Aggcgagcaacgcaaggagagctcaagagagaccacccctgcctccaggcacccgagttggacgagcgcttggtg gaaagagccactcaggaaagcacctTagaccactggagattcccccaagagcaaaacaaaacgaagcctgagttc aacgtcagaaaagtcgaaggtaccctgcctcccaacgtacttgtgattcaTcaatcgaaatacaagtgtgggatg aaaaaccatcatcctgaacagcaaagctccctgctaaacctctcttcgacgacccggacagatcaggagtccgtg aacactggcaccctcgcttctctgcaagggaggaccaggagatccaaagggaagaacaaacacagcaagagggct ctgcttgtgtgccagtga

HDUB8.5 deduced polypeptide sequence MEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLSSEARVDLCDDLAPVARQLAPRKKLPLSSRRP

AAVGAGLQNMGNTCYENASLQCLTYTPPLANYMLSREHSQTCQRPKCCMLCTMQAHITWALHSPGHVIQPSQALA

AGFHRGKQEDAHEFLMFTVDAMKKACLPGHKQVDHHSKDTTLIHQIFGGCWRSQIKCLHCHGISDTFDPYLDIAL

DIQAAQSVKQALEQLVKPEELNGENAYHCGLCLQRAPVSKTLTLHTFAKERILETQRPWWTRHKLAKSVQYAES

LDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHDGHYFSYVKAQEGQWYKMDDAKVTACSITSVLSQQAYVLFYIQK

SEWERHSESVSRGREPRALGAEDTDRRATQGELKRDHPCLQAPELDERLVERATQESTLDHWRFPQEQNKTKPEF

NVRKVEGTLPPNVLVIHQSKYKCGMKNHHPEQQSSLLNLSSTTRTDQESVNTGTLASLQGRTRRSKGKNKHSKRA

LLVCQ

Nucleotide sequence for HDUB8.6

Atggaagacgactcactctatttgggaggtgactggcagttcaatcacttttcaaaactcacatcttctcggcta gatgcagcttttgctgaaatccagcGgacttctctctctgaaaagtcaccactctcatctgagacccgtttcgac ctctgtgatgatttggctcctgtggcaagacagcttgctcccagggagaaGcttcctctgagtagcaggagacct gctgcggtgggggctgggctccagaagataggaaataccttctatgtgaacgtttccctgcagtgcctgacatac Acactgccgctttccaactacatgctgtcccgggaggactctcaaacgtgtcatcttcacaagtgctgcatgttc tgtactatgcaagctcacatcacatGggccctctaccgtcctggccatgtcatccagccctcacaggtattggct gctggcttccatagaggtgagcaggaggatgcccatgaatttctcatgttTactgtggatgccatgaaaaaggca tgccttcccgggcacaagcagctagatcatcactccaaggacaccaccctca ccaccaaatatttggagcgtat Tggagatctcaaatcaagtatctccactgccacggcatttcagacacctttgacccttacctggacatcgccctg gatatccaggcagctcagagtgtcaAgcaagctttggaacagttggtgaagcccaaagaactcaatggagagaat gcctatcattgtggtctttgtctccagaaggcgcctgcctccaagacgttAactttacccacttctgccaaggtc ctcattcttgtattgaagagattctccgatgtcacaggcaacaaacttgccaagaatgtgcaatatcctaagtgc Cgtgacatgcagccatacatgtctcagcagaacacaggacctcttgtctatgtcctctatgctgtgctggtccac gctgggtggagttgtcacaacggacAttacttctcttatgtcaaagctcaagaaggccagtggtataaaatggat gatgccgaggtcactgcctctggcatcacctctgtcctgagtcaacaggcCtatgtcctcttttacatccagaag agtgaatgggaaagacacagtgagagtgtgtcaagaggcagggaaccaagagcccttggtgctgaagacacagac Aggccagcaacgcaaggagagctcaagagagaccacccttgcctccaggtacccgagttggacgagcacttggtg gaaagagccactcaggaaagcacctTagaccactggaaattcccccaaaagcaaaacaaaacgaagcctgagttc aacgtcagaaaagttgaaggtaccctgcctcccaacgtacttgtgattcaTcaatcaaaatacaagtgtggtatg aaaaaccatcatcctgaacagcaaagctccctgctaaacctctcttcgacgaaaccgacagatcaggagtccatg Aacactggcacactcgcttctctgcaagggagcaccaggagatccaaagggaataacaaacacagcaagagatct ctgcttgtgtgccagtga

HDUB8.6 deduced polypeptide sequence

MEDDSLYLGGDWQFNHFSKLTSSRLDAAFAEIQRTSLSEKSPLSSETRFDLCDDLAPVARQLAPREKLPLSSRRP AAVGAGLQKIGNTFYVNVSLQCLTYTLPLSNYMLSREDSQTCHLHKCCMFCTMQAHITWALYRPGHVIQPSQVLA AGFHRGEQEDAHEFLMFTVDAMKKACLPGHKQLDHHSKDTTLIHQIFGAYWRSQIKYLHCHGISDTFDPYLDIAL DIQAAQSVKQALEQLVKPKELNGENAYHCGLCLQKAPASKTLTLPTSAKVLILVLKRFSDVTGNKLAKNVQYPKC RDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHNGHYFSYVKAQEGQWYKMDDAEVTASGITSVLSQQAYVLFYIQK SEWERHSESVSRGREPRALGAEDTDRPATQGELKRDHPCLQVPELDEHLVERATQESTLDHWKFPQKQNKTKPEF NVRKVEGTLPPNVLVIHQSKYKCGMKNHHPEQQSSLLNLSSTKPTDQESMNTGTLASLQGSTRRSKGNNKHSKRS LLVCQ

Nucleotide sequence for HDUB8.7

Atggaggacgactcactctacttgggaggtgagtggcagttcaaccacttttcaaaactcacatcttctcggcca gatgcagcttttgctgaaatccagcGgacttctctccctgagaagtcaccactctcatctgaggcccgtgtcgac ctctgtgatgatttggctcctgtggcaagacagcttgctcccaggaagaaGcttcctctgagtagcaggagacct gctgcggtgggggctgggctccagaatatgggaaatacctgctacgagaacgcttccctgcagtgcctgacatac

Acaccgccccttgccaactacatgctgtcccgggagcactctcaaacatgtcagcgtcccaagtgctgcatgctc tgtactatgcaagctcacatcacatGggccctccacagtcctggtcatgtcatccagccctcacaggcattggct gctggcttccatagaggcaagcaggaagatgcccatgaatttctcatgttCactgtggatgccatgaaaaaggca tgccttcccggccacaagcaggtagatcatcactctaaggacaccaccctcatccaccaaatatttggaggctgc

Tggagatctcaaatcaagtgtctccactgccacgggatttcagacacttttgacccttacctggacatcgccctg gatatccaggcagctcagagtgtcaAgcaagctttggaacagttggtgaagcccgaagaactcaatggagagaat gcctatcattgcggtctttgtctccagagggcgccagcctccaagacgttAactttacacacttctgccaaggtc ctcatccttgtcttgaagagattctccgatgtcacaggcaacaaacttgccaagaatgtgcaatatcctgagtgc Cttgacatgcagccatacatgtctcagcagaacacaggacctcttgtctatgtcctctatgctgtgctggtccac gctgggtggagttgtcacgatggacAttacttctcttatgtcaaagctcaagaaggccagtggtataaaatggat gatgccaaggtcactgcctgtagcatcacttctgtcctgagtcaacaggcCtatgtcctcttttacatccagaag agtgaatgggaaagacacagtgagagtgtgtcaagaggcagggaaccaagagccctcggcgctgaagacacagac Aggcgagcaacgcaaggagagctcaagagagaccacccctgcctccaggcacccgagttggacgagcgcttggtg gaaagagccactcaggaaagcacctTagaccactggagattcccccaagagcaaaacaaaacgaagcctgagttc aacgtcagaaaagtcgaaggtaccctgcctcccaacgtacttgtgattcaTcaatcgaaatacaagtgtgggatg aaaaaccatcatcctgaacagcaaagctccctgctaaacctctcttcgacgacccggacagatcaggagtccgtg aacactggcaccctcgcttctctgcaagggaggaccaggagatccaaagggaagaacaaacacagcaagagggct ctgcttgtgtgccagtga

HDUB8.7 deduced polypeptide sequence MEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLSSEARVDLCDDLAPVARQLAPRKKLPLSSRRP AAVGAGLQNMGNTCYENASLQCLTYTPPLANYMLSREHSQTCQRPKCCMLCTMQAHITWALHSPGHVIQPSQALA AGFHRGKQEDAHEFLMFTVDAMKKACLPGHKQVDHHSKDTTLIHQIFGGCWRSQIKCLHCHGISDTFDPYLDIAL DIQAAQSVKQALEQLVKPEELNGENAYHCGLCLQRAPASKTLTLHTSAKVLILVLKRFSDVTGNKLAKNVQYPEC LDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHDGHYFSYVKAQEGQWYKMDDAKVTACSITSVLSQQAYVLFYIQK SEWERHSESVSRGREPRALGAEDTDRRATQGELKRDHPCLQAPELDERLVERATQESTLDHWRFPQEQNKTKPEF NVRKVEGTLPPNVLVIHQSKYKCGMKNHHPEQQSSLLNLSSTTRTDQESVNTGTLASLQGRTRRSKGKNKHSKRA LLVCQ

Nucleotide sequence for HDUB8.8

Atggaagacgactcactctatttgggaggtgactggcagttcaatcacttttcaaaactcacatcttctcggcta gatgcagcttttgctgaaatccagcGgacttctctctctgaaaagtcaccactctcatctgagacccgtttcgac ctctgtgatgatttggctcctgtggcaagacagcttgctcccagggagaaGcttcctctgagtagcaggagacct gctgcggtgggggctgggctccagaagataggaaataccttctatgtgaacgtttccctgcagtgcctgacatac Acactgccgctttccaactacatgctgtcccgggaggactctcaaacgtgtcatcttcacaagtgctgcatgttc tgtactatgcaagctcacatcacatGggccctctaccgtcctggccatgtcatccagccctcacaggtattggct gctggcttccatagaggtgagcaggaggatgcccatgaatttctcatgttTactgtggatgccatgaaaaaggca tgccttcccgggcacaagcagctagatcatcactccaaggacaccaccctcatccaccaaatatttggagcgtat Tggagatctcaaatcaagtatctccactgccacggcatttcagacacctttgacccttacctggacatcgccctg gatatccaggcagctcagagtgtcaAgcaagctttggaacagttggtgaagcccaaagaactcaatggagagaat gcc atcattgtggtctttgtctccagaaggcgcctgcctccaagacgttAactttacccacttctgccaaggtc ctcattcttgtattgaagagattctccgatgtcacaggcaacaaacttgccaagaatgtgcaatatcctaagtgc Cgtgacatgcagccatacatgtctcagcagaacacaggacctcttgtctatgtcctctatgctgtgctggtccac gctgggtggagttgtcacaacggacAttacttctcttatgtcaaagctcaagaaggccagtggtataaaatggat gatgccgaggtcactgcctctggcatcacctctgtcctgagtcaacaggcCtatgtcctcttttacatccagaag agtgaatgggaaagacacagtgagagtgtgtcaagaggcagggaaccaagagcccttggtgctgaagacacagac Aggccagcaacgcaaggagagctcaagagagaccacccttgcctccaggtacccgagttggacgagcacttggtg gaaagagccactcaggaaagcacctTagaccactggaaattcccccaaaagcaaaacaaaacgaagcctgagttc aacgtcagaaaagttgaaggtaccctgcctcccaacgtacttgtgattcaTcaatcaaaatacaagtgtggtatg aaaaaccatcatcctgaacagcaaagctccgtgctaaacctctcttcgacgaaaccgacagatcaggagtccatg aacactggcacactcgcttctctgcaagggagcaccaggagatccaaagggaataacaaacacagcaagagatct ctgcttgtgtgccagtga

HDUB8.8 deduced polypeptide sequence

MEDDSLYLGGDWQFNHFSKLTSSRLDAAFAEIQRTSLSEKSPLSSETRFDLCDDLAPVARQLAPREKLPLSSRRP AAVGAGLQKIGNTFYVNVSLQCLTYTLPLSNYMLSREDSQTCHLHKCCMFCTMQAHITWALYRPGHVIQPSQVLA AGFHRGEQEDAHEFLMFTVDAMKKACLPGHKQLDHHSKDTTLIHQIFGAYWRSQIKYLHCHGISDTFDPYLDIAL DIQAAQSVKQALEQLVKPKELNGENAYHCGLCLQKAPASKTLTLPTSAKVLILVLKRFSDVTGNKLAKNVQYPKC- RDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHNGHYFSYVKAQEGQWYKMDDAEVTASGITSVLSQQAYVLFYIQK SEWERHSESVSRGREPRALGAEDTDRPATQGELKRDHPCLQVPELDEHLVERATQESTLDHWKFPQKQNKTKPEF NVRKVEGTLPPNVLVIHQSKYKCGMKNHHPEQQSSVLNLSSTKPTDQESMNTGTLASLQGSTRRSKGNNKHSKRS LLVCQ Nucleotide sequence for HDUB8.11 Atggaggacgactcactctacttgggaggtgagtggcagttcaaccacttttcaaaactcacatcttctcggcca gatgcagcctttgctgaaatccagcGgacttctctccctgagaagtcacaactctcaactgagacccgcgtcgac ttctgcgatgatttggccgctgtggcaagacagctcgctcccagggagaaGcttcctctgagtagcaggagacct gctgcggtgggggctgggctccagaatatgggaaatacctgctacgtgaacgcttcccagcagtgtctgacatac Ataccgccccttgccaactacatgctgtcccgggagcactctcaaacatgtcatcgtcacaagtgctgcatgctc tgtaccatggaagctcacatcacatGgcccctccacattcctggccatgtcatccagccctcacaggcattggct gctggcttccatagaggcaagcaggaagctgcccttgaatttctcatgttCactgtggatgccatgaaaaaggca tgccttcccgggcacaagcagatcctcatcctcgtatggaagagattctccgatgtcacaggcaacaaaattgcc Aagaatgtgcaatatcctgagtgccttgacatgcagccatacatgtctcagcagaacacaggacctcttgtctat gtcctctatgctgtgctggtccacgCcgggtggagttgtcacaacggacattacttctcttatgtcaaagttcaa gaaggccagtggtataaaatggatgatgccgagaagagtgaatgggaaagAcacagtgagagtgtgtcaagaggc agggaaccaagagccctcggcgctgaagacacagacaggcgagcaacgcaaggagagctcaagagagactacccc Tgcctccaggtacccgagttggacgagcacttggtggaaagagccactcaggaaagcaccttagaccactggaaa ttcctccaagagcaaaacaaaacgaAgcctgagttcaacgtcagaaaacttgaaggtaccctgcctcccaacgta cttgtgat catcaatcaaaatacaagtgtgggatgaaaaaccatca ccTgaacagcaaagctccctgctaaac ctctcttcgacgaacccgacagatcaggagtccatgaacactggcacactcgcttctctgcaagggaggaccagg agatccaaagggaagaacaaacactgcaagagggctctgcttgtgtgccagtga

HDUB8.11 deduced polypeptide sequence

MEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSQLSTETRVDFCDDLAAVARQLAPREKLPLSSRRP AAVGAGLQNMGNTCYVNASQQCLTYIPPLANYMLSREHSQTCHRHKCCMLCTMEAHITWPLHIPGHVIQPSQALA AGFHRGKQEAALEFLMFTVDAMKKACLPGHKQILILVWKRFSDVTGNKIAKNVQYPECLDMQPYMSQQNTGPLVY VLYAVLVHAGWSCHNGHYFSYVKVQEGQWYKMDDAEKSEWERHSESVSRGREPRALGAEDTDRRATQGELKRDYP CLQVPELDEHLVERATQESTLDHWKFLQEQNKTKPEFNVRKLEGTLPPNVLVIHQSKYKCGMKNHHPEQQSSLLN LSSTNPTDQESMNTGTLASLQGRTRRSKGKNKHCKRALLVCQ

Nucleotide sequence for HDUB4.4 sequence atggaggagg actcactcta cttgggtggt gagtggcagt tcaaccactt ttcaaaactc acatcttctc ggctcgatgc agcttttgct gaaatccagc ggacttctct ccctgagaag tcaccactct catgtgagac ccgtgtcgac ctctgtgatg atttggttcc tgaggcaaga cagcttgctc ccagggagaa gcttcctctg agtagcagga gacctgctgc ggtgggggct gggctccaga atatgggaaa tacctgctac gtgaacgctt ccttgcagtg cctgacatac acaccgcccc ttgccaacta catgctgtcc cgggagcact ctcaaacgtg tcatcgtcac aagggctgca tgctctgtac tatgcaagct cacatcacac gggccctcca caatcctggc cacgtcatcc agccctcaca ggcattggct gctggcttcc atagaggcaa gcaggaagat gcccatgaat ttctcatgtt cactgtggat gccatgaaaa aggcatgcct tcccgggcac aagcaggtag atcatccctc taaggacacc accctcatcc accaaatatt tggaggctac tggagatctc aaatcaagtg tctccactgc cacggcattt cagacacttt tgacccttac ctggacatcg ccctggatat ccaggcagct cagagtgtcc agcaagcttt ggaacagttg gtgaagcccg aagaactcaa tggagagaat gcctatcatt gtggtgtttg tctccagagg gcgccggcct ccaagacgtt aactttacac acttctgcca aggtcctcat ccttgtattg aagagattct ccgatgtcac aggcaacaag attgccaaga atgtgcaata tcctgagtgc cttgacatgc agccatacat gtctcagcag aacacaggac ctcttgtcta tgtcctctat gctgtgctgg tccatgctgg gtggagttgt cacaacggac attacttctc ttatgtcaaa gctcaagaag gccagtggta taaaatggat gatgccgagg tcaccgcctc ttagcatcac atctgtcctg agtcaacagg cctacgtcct cttttacatc cagaagagtg aatgggaaag acacagtgag agtgtgtcaa gaggcaggga accaagagcc cttggcgcag aagacacaga caggcgagta acgcaaggag agctcaagag agaccacccc tgactccagg cccccgagtt ggacgagcac ttggtggaaa gagccactca ggaaagcacc ttagaccact ggaaattcct tcaagagcaa aacaaaacga agcctgagtt caacgtcaga aaagtcgaag gtaccctgcc tcccgacgta cttgtgattc atcaatcaaa atacaagtgt gggatgaaga accatcatcc tgaacagcaa agctccctgc taaacctctc ttcgacgacc ccgacacatc agcagtccat gaacaatggc acactcgctt ccctgcgagg gagggccagg agatccaaag ggaagaacaa acacagcaag agggctctgc ttgtgtgcca gtga

hDUB4.4 Deduced polypeptide sequence

MEEDSLYLGG EWQFNHFSKL TSSRLDAAFA EIQRTSLPEK SPLSCETRVD LCDDLVPEAR QLAPREKLPL SSRRPAAVGA GLQNMGNTCY VNASLQCLTY TPPLANYMLS REHSQTCHRH KGCMLCTMQA HITRALHNPG HVIQPSQALA AGFHRGKQED AHEFLMFTVD AMKKACLPGH KQVDHPSKDT TLIHQIFGGY WRSQIKCLHC HGISDTFDPY LDIALDIQAA QSVQQALEQL VKPEELNGEN AYHCGVCLQR APASKTLTLH TSAKVLILVL KRFSDVTGNK IAKNVQYPEC LDMQPYMSQQ NTGPLVYVLY AVLVHAGWSC HNGHYFSYVK AQEGQWYKMD DAEVTAS

Nucleotide sequence for hDUB 4 . 9 atggaggacg actcactcta cttgggaggt gagtggcagt tcaaccactt ttcaaaactc acatctcctc ggcccgatgc agcttttgct gaaatccagc ggacttctct ccctgagaag tcaccactct catgtgagac ccgtgtcgac ctctgtgatt atttggctcc tgtggcaaga cagcttgctc ccagggagaa gcttcctctg agtagcagga gacctgctgc ggtgggggct gggctccaga atatgggaaa tacctgctac gtgaacgctt ccttgcagtg cctgacatac acaccgcccc ttgccaacta catgctgtcc cgggagcact ctcaaacgtg tcatcgtcac aagggctgca tgctctgtac tatgcaagct cacatcacac gggccctcca caatcctggc cacgtcatcc agccctcaca ggcattggct gctggcttcc atagaggcaa gcaggaagat gcccatgaat ttctcatgtt cactgtggat gccatgaaaa aggcatgcct tcccgggcac aagcaggtgg atcatcactc taaggacacc accctcatcc accaaatatt tggaggctac tggagatctc aaatcaagtg tctccactgc cacggcattt cagacacttt tgacccttac ctggacatcg ccctggatat ccaggcagct cagagtgtcc agcaagcttt ggaacagttg gtgaagcccg aagaactcaa tggagagaat gcctatcatt gtggtgtttg tctccagagg gcgccggcct ccaagacgtt aactttacac acctctgcca aggtcctcat ccttgtattg aagagattct ccgatgtcac aggcaacaag attgccaaga atgtgcaata tcctgagtgc cttgacatgc agccatacat gtctcagcag aacacaggac ctcttgtcta tgtcctctat gctgtgctgg tccacgctgg gtggagttgt cacaacggac attacttctc ttatgtcaaa gctcaagaag gccagtggta taaaattgat gatgccgagg tcaccgcctc tagcatcact tctgtcctga ctcaacaggc ctacgtcctc ttttacatcc agaagagtga atgggaaaga cacagtgaga gtgtgtcaag aggcagggaa ccaagagccc ttggctctga agactaa hDUB4.9 deduced polypeptide sequence MEDDSLYLGG EWQFNHFSKL TSPRPDAAFA EIQRTSLPEK SPLSCETRVD LCDYLAPVAR QLAPREKLPL SSRRPAAVGA GLQNMGNTCY VNASLQCLTY TPPLANYMLS REHSQTCHRH KGCMLCTMQA HITRALHNPG HVIQPSQALA AGFHRGKQED AHEFLMFTVD AMKKACLPGH KQVDHHSKDT TLIHQIFGGY WRSQIKCLHC HGISDTFDPY LDIALDIQAA QSVQQALEQL VKPEELNGEN AYHCGVCLQR APASKTLTLH TSAKVLILVL KRFSDVTGNK IAKNVQYPEC LDMQPYMSQQ NTGPLVYVLY AVLVHAGWSC HNGHYFSYVK AQEGQWYKID DAEVTASSIT SVLTQQAYVL FYIQKSEWER HSESVSRGRE PRALGSED

Nucleotide sequence for hDUB8.2 sequence atgcggccag agagcccgtc atttgaagac tcggaagaga tagcgtcttt ctgcaacctg cggtcccagc cgaaaaacct tgtgatcctt gttccgggcg acatggagga cgactcactc tacttgggag gtgagtggca gttcaaccac ttttcaaaac tcacatcttc tcggccagat gcagcttttg ctgaaatcca gcggacttct ctctctgaga agtcatcact ctcatctgag acccgcgtcg acctctgtga tgatttggct cctgtggcaa gacagctcgc tcccagggag aagcttcctc tgagtagcag gagacctgct gcggtggggg ctgggctcca gaatatggga aatacctgct acgtgaacgc ttccctgcag tgcctgacat acacaccgcc ccttgccaac tacatgctgt cccgggagca ctctcaaacg tgtcatcgtc acaagtgctg catgctctgt actatgcaag ctcacatcac atggcccctc cacagtcctg gccatgtcat ccagccctca caggtgttgg ctgctggctt ccatagaggc gagcaggaag atgcccatga atttctcatg ttcactgtgg atgccatgaa aaaggcattc cttcccgggc acaagcattt agataatcac tctaaggaca ccaccctcat ccaccaaata tttggagggt actggagatc tcacatcaac tgtttccact gccacgggat ttcagacacc tttgaccctt acctggacat cgccctggat atccaggcag ctcagagtgt caagcaagct ttgtaacagt tggtgaagcc cgaagaactc aatggataaa atgcctatca ttgtggtctt tgtctccaga aggcgcctgc ctccaggacg ttaactttac acacttctgc caaggtcctc atccttgtat tgaagagatt ctctgaggtc acaggcaaca aacttgccaa gaatgtgcaa tatcctgagt gccttgacat gcagccatac atgtctcagc agaacacagg acctcttgtc tatgtcctct atgctgtgct ggtccacgct gggtggagtt gtcacaacgg acattactta tcttatgtca aactcaagaa ggccattggt ataaaatgga tgatgccgag gtcactgcct ccggtatcac ttctgtcctg agtcaacagg cctatgtcct cttttacatc cagaagaatg aatttggaag acccagttac agtgtgtcca taggcaggga accaagagct ctttgcgtga aggcaagtga attgtgtgtg aaataaaatg tcatgaataa atcttgcagt ggagtattta tttgtctcac tttgtaatca gtgaatgagc tttaaccaat atcaatgcct agtgcctacc ccccagagat aagaacttcc actctcttat gtgtaaccat ggcctctgga ttgcttatga ctctgaagat aattctcctt tcccccaacg tttcagaatc acttcaggtg gtggtaacag ataacacatc agtccctttc tctctctttt ctcttcactc aggaaaactc tcactgagac aaaggaaaat cctatggttt actggggagg aagaattccc tcaggagtga aattggtggc tccttcctcc ctgtcaagtc tcttcctcag gattgcccct ttgtctcttc aggact

hDUB8.2 dedeuced polypeptide sequence

MRPESPSFED SEEIASFCNL RSQPKNLVIL VPGDMEDDSL YLGGEWQFNH FSKLTSSRPD AAFAEIQRTS LSEKSSLSSE TRVDLCDDLA PVARQLAPRE KLPLSSRRPA AVGAGLQNMG NTCYVNASLQ CLTYTPPLAN YMLSREHSQT CHRHKCCMLC TMQAHITWPL HSPGHVIQPS QVLAAGFHRG EQEDAHEFLM FTVDAMKKAF LPGHKHLDNH SKDTTLIHQI FGGYWRSHIN CFHCHGISDT FDPYLDIALD IQAAQSVKQA L

Nucleotide sequence for hDUB 8.9

atggaggaag actcactcta cttgggaggt gagtggcagt tcaaccactt ttcaaaactc acatcttctc agccagatgc agcttttcct gaaatccagc ggacttctct ccctgagaag tcaccactct catcggagac ccgtgtcgac ctctgtgacg atttggctcc tgtgacaaga cagcttgctc ccagggagaa gcttcctccg agtagcagga gacctgctgc ggtgggagct ggtctccaga atatgggaaa tacctgccac ttgaatgctt ccctgcagtg cctgacatac acaccgcccc ttgccaacta catgctgtcc tgggagctct ctcaaatgtg tcatcgtccc aagtgctgca tgctctgtat tatggaagct cacagcacac gggcacctcc accgtcctgg ccatgtcatc cagccctcac aggcattggc tgctgacttc catagagaca agcaggaaga tgcccatgaa tttctcatat tcactgtgga tgccattaga aaggcatgcc ttcccgggca caagcagcta gatcatcact gcaaggacac catcctcatc caccaaatat ttggagggta ctagagatct caaatcaagt gtctctactt ccacggcatt tcagacacct tcgaccctta cctggatatc gccctggata tccaggcagc tcagagtgtc aagcaagctt tggaacagtt ggtgaagccc gaagaactca atggagagaa tgcctatcat tgtggtcttt gtctccagaa ggcgcctgcc gccaagacgt taactttacc cacttctgcc aaggtcctca tccttgtctt gaagagattc tccgatgtca caggcaacaa acttgccaag aatctgcaat atcctgagtg cgttgacatg cagccataca tgtctcagca gaacacagga cctcttttct atgtcctcta tgctgttctc gtcatcaccg ggtggagttg tcacaacgga cattacttct cttgtgtcaa actcaagaag gccagtggta taaaatggat gatgccgagg tcactgcctc tggtatcact tctccttaga gtcaacaggc ctatgtcctc ttttacatcc agaagaatga atttggaaga cccagttaca gggtgtccgc aggcagagaa ccaagagctc tttgtgctga agacaattga attgtggtga aataatatgt catgaataaa tcttgcagca gatttatttg tctcactttg taatcagtga atgagcttta acgaatatca atgcctagtg cctacccccc agagataaga acttccagtt tctcatgtgt aatcatggca tctggattgc tcatgattct gaagataatt ctcctgtccc ccaaagtttc agaatcactt caggtggtag aaacagataa cacatcagtc cctttctctc tcttttctct tea hDUBδ .9 Deduced polypeptide sequence MEDDSLYLGG EWQFNHFSKL TSSRPDAAFA EIQRTSLSEK SSLSSETRVD LCDDLAPVAR QLAPREKLPL SSRRPAAVGA GLQNMGNTCY VNASLQCLTY TPPLANYMLS REHSQTCHRH KCCMLCTMQA HITWPLHSPG HVIQPSQVLA AGFHRGEQED AHEFLMFTVD AMKKAFLPGH KHLDNHSKDT TLIHQIFGGY WRSHINCFHC HGISDTFDPY LDIALDIQAA QSVKQALEQL VKPEELNG

Nucleotide sequence for hDUB 8.10 atggaggacg actcactcta cttgggaggt gagtggcagt tcaaccactt ttcaaaactc acatcttctc ggccagatgc agcttttgct gaaatccagc ggacttctct ctctgagaag tcatcactct catctgagac ccgcgtcgac ctctgtgatg atttggctcc tgtggcaaga cagctcgctc ccagggagaa gcttcctctg agtagcagga gacctgctgc ggtgggggct gggctccaga atatgggaaa tacctgctac gtgaacgctt ccctgcagtg cctgacatac acaccgcccc ttgccaacta catgctgtcc cgggagcact ctcaaacgtg tcatcgtcac aagtgctgca tgctctgtac tatgcaagct cacatcacat ggcccctcca cagtcctggc catgtcatcc agccttcaca ggtgttggct gctggcttcc atagaggcga gcaggaagat gcccatgaat ttctcatgtt cactgtggat gccatgaaaa aagcattcct tcccgggcac aagcatttag ataatcactc taaggacacc accctcatcc accaaatatt tggagggtac tggagatctc acatcaactg tttccactgc catgggattt cagacacctt tgacccttac ctggacatcg ccctggatat ccaggcagct cagagtgtca agcaagcttt ggaacagttg gtgaagcccg aagaactcaa tggataaaat gcctatcatt gtggtctttg tctccagaag gcgcctacct ccaggacgtt aactttacac acttctgcca aggtcctcat ccttgtattg aagagattct ctgatgtcac aggcaacaaa cttgccaaga atgtgcaata tcctgagtgc cttgacatgc agccatacat gtctcagcag aacacaggac ctcttgtcta tgtcctctat gctgtgctgg tccacgctgg gtggagttgt cacaacggac attacttatc ttatgtcaaa ctcaagaagg ccattggtat aaaatggatg atgccgaggt cactgcctcc ggtatcactt ctgtcctgag tcaacaggcc tatgtcctct tttacatcca gaagaatgaa tttggaagac ccagttacag tgtgtccata ggcagggaac cgagagctct ttgcgtgaag gcaagtgaat tgtgtgtgaa ataaaatgtc atgaataaat cttgcagtgg agtatttatt tgtctcactt tgtaatcagt gaatgagctt taaccaatat caatgcctag tgcctacccc ccagagataa gaacttccac tctcttatgt gtaaccatgg cctctggatt gcttatgact ctgaagataa ttctcctttc ccccaacgtt tcagaatcac ttcaggtggt ggtaacagat aacacatcag tccctttctc tctcttttct cttcactcag gaaaactctc actgagacaa aggaaaatcc tatggtttac tggggaggaa gaattccctc aggagtgaaa ttggtggctc cttcctccct gtcaagtctc ttcctcagga ttgccccttt gtctcttcag gactctgctc atcaggcccg agatgccccc tggttgtgca tacctggcct gtgaagaaat a hDUB8.10 Deduced polypeptide sequence MEEDSLYLGG EWQFNHFSKL TSSQPDAAFP EIQRTSLPEK SPLSSETRVD LCDDLAPVTR QLAPREKLPP SSRRPAAVGA GLQNMGNTCH LNASLQCLTY TPPLANYMLS WELSQMCHRP KCCMLCIMEA HSTRAPPPSW PCHPALTGIG C

Table 24. Deduced aAmino acid alignment ofhDUB4.10 and hDUB4.11.

hDUB4.10 MCIRTGSPCDVCENYSVMSMTGRQLIDWAPLKIGYEHSSTPMPREHVHFRQHYNFGTKCA 60 hDUB4.11 MCIRTGSPCDVCENYSVMSMTGRQLIDWAPLKIGYEHSSTPMPRT-LYIRHRK 52

******************************************** ...*.. hDUB4.10 NCNSTIQCVTGNGGNIADPERSMRESRICTAYFGLFPLKQGPVLKMVISLGQRINRLNVE 120 hDUB4.11 PSDGAHLAHEK TRE 66

..:*.::*. : . * hDUB4.10 RLSLEGKKIRCAKYYTSLTILRSESALSTSCPSVAERMMAAAKRIASFCNLRSQQKNLVI 180 hDUB4.11 RNGAKGKKIRCAKYYTSLTILRSESALSSSCPSVAERMMAAAK 109

* .A********************** .************** hDUB4.10 LVPVDMEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLSCETRVDLCDDL 240 hDUB4.11 IDMEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLS- -YDL 158

. ********************************************* ** ** hDUB4.10 APVARQLAPREKLPLSSRRPAAVGAGLQNMGNTCYVNASLQCLTYTTPLANYMLSREHSQ 300 hDUB4.11 APVARQLAPREKLPLSSRRPAAVGAGLQNMGNTCYVNASLQCLTYTPPLANYMLSREHSQ 218 _************_****_***_***_****_****_*****_**_****_***** _*****_****_**** hDUB4.10 TCHRHKGCMLCTMQAHITRALHNPGHVIQPSQALAAGFHRGKQEDAHEFLMFTVDAMKKA 360 hDUB4.11 TCHRHKGCMLCTMQAHITRALHNPGHVIQPSQALAAGFHRGKQEDAHEFLMFTVDAMKKA 278 ************************************************************ hDUB4.10 CLPGHKQVDHHSKDTTLIHQIFGGYWRSQIKCLHCHGISDTFDPYLDIALDIQAAQSVQQ 420 hDUB4.11 CLPRHKQVDHHSKDTTLIHQIFGGYWRSQIKCLHCHGISDTFDPYLDIALDIQAAQSVQQ 338 *** ******************************************************** hDUB4.10 ALEQLVKPEELNGENAYHSGVCLQRAPASKTLTLHTSAKVLILVLKRFSDVTGNKIAKNV 480 hDUB4.11 ALEQLVKPEELNGENAYHCGVCLQRAPASKTLTLHTSAKVLILVLKRFSDVTGNKIAKNV 398 ****************** _ ***************************************** hDUB4.10 QYPECLDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHNGHYFSYVKAQEGQWYKMDDAEVT 540 hDUB4.11 QYPECLDMQPYMSQQNTGPLVYVLYAVLVHAEWSCHNGHYFSYVKAQEGQWYKMDDAEVT 458 ******************************* **************************** hDUB4.10 AASITSALSQQAYVLFYIQKSEWERHSESVSRGREPRALGTEDTDRRATQGELKRDHPCL 600 hDUB4.11 AASITSVLSQQAYVLFYIQKSEWERHSESVSRGREPRALGAEDTDRRATQGELKRDHPCL 518 ****** ********************************* .******************* hDUB4.10 QAPELDEHLVERATQESTLDHWKFLQEQNKTKPEFNVRKVEGTLPPDVLVIHQSKYKCGM 660 hDUB4.11 QAPELDEHLVERATQESTLDHWKFLQEQNKTKPEFNVRKVKGTLPPDVLVIHQSKYKCGM 578 **************************************** . ******************* hDUB4.10 KNHHPEQQSSLLNLSSSTPTHQESMNTGTLASLRGRARRSKGKNKHSKRALLVCQ 715 hDUB4.11 KNHHPEQQSSLLNLSSSTPTHQESMNTGTLASLRGRARRSKGKNKHSKRALLVC- 632 ******************************************************

Table 25. Nucleotide sequence alignment of hDUB4.5, hDUB4.8 and hDUB8.2 In frame termination codons in hDUB8.2 are underlined hDUB4.5 ATGCG-CCAGAGAGCTCGTCATTTGAAGACTCTCTCGGAAGGGATAGCGTCTTTCTGCAA 59 hDUB4.8 ATGCG-CCAGAGAGCTCGTCATTTGAAGACTCTCTCGGAAGGGATAGCGTCTTGCTGCAA 59 hDUB8.2 ATGCGGCCAGAGAGCCCGTCATTTGAAGA CTCGGAAGAGATAGCGTCTTTCTGCAA 56

_{***** ********* ******}*_{****** ******** *********** ******} hDUB₄.5 CCTGCGGTCCCAGCAGAAAAACCTTGTGATCCTTGTTCCAGTCGACATGGAGGAAGACTC 119 hDUB .8 ACTGCGGTCCCAGCAGAAAAACCTTGTGATCCTTGTTCCAGTCGACATGGAGGACGACTC 119 hDUB8.2 CCTGCGGTCCCAGCCGAAAAACCTTGTGATCCTTGTTCCGGGCGACATGGAGGACGACTC 116 _{************* ************************ * ************ *****} hDUB4.5 ACTCTACTTGGGAGGTGAGTGGCAGTTCAACCACTTTTCAAAACTCACATCTTCTCGGCC 179 hDUB4.8 ACTCTACTTGGGAGGTGAGTGGCAGTTCAACCACTTTTCAAAACTCACATCTTCTCGGCC 179 hDUB8.2 ACTCTACTTGGGAGGTGAGTGGCAGTTCAACCACTTTTCAAAACTCACATCTTCTCGGCC 176 _{************************************************************} hDUB4.5 CGATGCAGCTTTTGCTGAAATCCAGCGGACTTCTCTCCCTGAGAAGTCACCACTCTCATG 239 hDUB4.8 CGATGCAGCTTTTGCTGAAATCCAGCGGACTTCTCTCCCTGAGAAGTCACCACTCTCATG 239 hDUB8.2 AGATGCAGCTTTTGCTGAAATCCAGCGGACTTCTCTCTCTGAGAAGTCATCACTCTCATC 236 _{************************************ *********** *********} hDUB4.5 TGAGACCCGTGTCGACCTCTGTGATGATTTGGCTCCTGTGGCAAGACAGCTTGCTCCCAG 299 hDUB4.8 TGAGACCCGTGTCGACCTCTGTGATGATTTGGCTCCTGTGGCAAGACAGCTTGCTCCCAG 299 hDUB8.2 TGAGACCCGCGTCGACCTCTGTGATGATTTGGCTCCTGTGGCAAGACAGCTCGCTCCCAG 296 _{********* ***************************************** ********} hDUB4.5 GGAGAAGCTTCCTCTGAGTAACAGGAGACCTGCTGCGGTGGGGGCTGGGCTCCAGAATAT 359 hDUB4.8 GGAGAAGCTTCCTCTGAGTAGCAGGAGACCTGCTGCGGTGGGGGCTGGGCTCCAGAATAT 359 hDUB8.2 GGAGAAGCTTCCTCTGAGTAGCAGGAGACCTGCTGCGGTGGGGGCTGGGCTCCAGAATAT 356 _{******************** ***************************************} hDUB4.5 GGGAAATACCTGCTACGTGAACGCTTCCTTGCAGTGCCTGACATACACACCGCCCCTTGC 419 hDUB4.8 GGGAAATACCTGCTACGTGAACGCTTCCTTGCAGTGCCTGACATACACACCGCCCCTTGC 419 hDUB8.2 GGGAAATACCTGCTACGTGAACGCTTCCCTGCAGTGCCTGACATACACACCGCCCCTTGC 416 _{**************************** *******************************} hDUB4.5 CAACTACATGCTGTCCCGGGAGCACTCTCAAACGTGTCATCGTCACAAGGGCTGCATGCT 479 hDUB4.8 CAACTACATGCTGTCCCGGGAGCACTCTCAAACGTGTCATCGTCACAAGGGCTGCATGCT 479 hDUB8.2 CAACTACATGCTGTCCCGGGAGCACTCTCAAACGTGTCATCGTCACAAGTGCTGCATGCT 476 _{************************************************* **********} hDUB4.5 CTGTACGATGCAAGCTCACATCACACGGGCCCTCCACAATCCTGGCCACGTCATCCAGCC 539 hDUB4.8 CTGTACGATGCAAGCTCACATCACACGGGCCCTCCACAATCCTGGCCACGTCATCCAGCC 539 hDUB8.2 CTGTACTATGCAAGCTCACATCACATGGCCCCTCCACAGTCCTGGCCATGTCATCCAGCC 536 _{****** ****************** ** ********* ********* ***********} hDUB4.5 CTCACAGGCATTGGCTGCTGGCTTCCATAGAGGCAAGCAGGAAGATGCCCATGAATTTCT 599 hDUB4.8 CTCACAGGCATTGGCTGCTGGCTTCCATAGAGGCAAGCAGGAAGATGCCCATGAATTTCT 599 hDUB8.2 CTCACAGGTGTTGGCTGCTGGCTTCCATAGAGGCGAGCAGGAAGATGCCCATGAATTTCT 596 _{******** ************}*_{*********** *************************} hDUB4.5 CATGTTCACTGTGGATGCCATGAAAAAGGCATGCCTTCCCGGGCACAAGCAGGTGGATCA 659 hDUB4.8 CATGTTCACTGTGGATGCCATGAAAAAGGCATGCCTTCCCGGGCACAAGCAGGTAGATCA 659 hDUB8.2 CATGTTCACTGTGGATGCCATGAAAAAGGCATTCCTTCCCGGGCACAAGCATTTAGATAA 656 _{**********************}*_{********* ****************** * *** *} hDUB4.5 TCACTCTAAGGACACCACCCTCATCCACCAAATATTTGGAGGCTACTGGAGATCTCAAAT 719 hDUB4.8 TCACTCTAAGGACACCACCCTCATCCACCAAATATTTGGAGGCTACTGGAGATCTCAAAT 719 hDUB8.2 TCACTCTAAGGACACCACCCTCATCCACCAAATATTTGGAGGGTACTGGAGATCTCACAT 716 _{**********************}*_{******************* ************** **} hDUB4.5 CAAGTGTCTCCACTGCCACGGCATTTCAGACACTTTTGACCCTTACCTGGACATCGCCCT 779 hDUB4.8 CAAGTGTCTCCACTGCCACGGCATTTCAGACACTTTTGACCCTTACCTGGACATCGCCCT 779 hDUB8.2 CAACTGTTTCCACTGCCACGGGATTTCAGACACCTTTGACCCTTACCTGGACATCGCCCT 776 _{*** *** ************* *********** **************************} hDUB4.5 GGATATCCAGGCAGCTCAGAGTGTCCAGCAAGCTTTGGAACAGTTGGTGAAGCCCGAAGA 839 hDUB4.8 GGATATCCAGGCAGCTCAGAGTGTCCAGCAAGCTTTGGAACAGTTGGTGAAGCCCGAAGA 839 hDUB8.2 GGATATCCAGGCAGCTCAGAGTGTCAAGCAAGCTTTGTAACAGTTGGTGAAGCCCGAAGA 836 _{************************* *********** **********************} hDUB4.5 ACTCAATGGAGAGAATGCCTATCATTGTGGTGTTTGTCTCCAGAGGGCGCCGGCCTCCAA 899 hDUB4.8 ACTCAATGGAGAGAATGCCTATCATTGTGGTGTTTGTCTCCAGAGGGCGCCGGCCTCCAA 899 hDUB8.2 ACTCAATGGATAAAATGCCTATCATTGTGGTCTTTGTCTCCAGAAGGCGCCTGCCTCCAG 896 _{********** * *********}*_{******** ************ ****** *******} hDUB4.5 GACGTTAACTTTACACACCTCTGCCAAGGTCCTCATCCTTGTATTGAAGAGATTCTCCGA 959 hDUB4.8 GACGTTAACTTTACACACCTCTGCCAAGGTCCTCATCCTTGTATTGAAGAGATTCTCCGA 959 hDUB8.2 GACGTTAACTTTACACACTTCTGCCAAGGTCCTCATCCTTGTATTGAAGAGATTCTCTGA 956 _{****************** ***}*_{********************************** **} hDUB4.5 TGTCACAGGCAACAAGATTGACAAGAATGTGCAATATCCTGAGTGCCTTGACATGAAGCT 1019 hDUB4.8 TGTGACAGGCAACAAGATTGCCAAGAATGTGCAATATCCTGAGTGCCTTGACATGCAGCC 1019 hDUB8.2 GGTCACAGGCAACAAACTTGCCAAGAATGTGCAATATCCTGAGTGCCTTGACATGCAGCC 1016 _{** *********** *** ********************************** ***} hDUB4.5 ATACATGTCTCAGACGAACTCAGGACCTCTCGTCTATGTCCTCTATGCTGTGCTGGTCCA 1079 hDUB4.8 ATACATGTCTCAGCAGAACACAGGACCTCTTGTCTATGTCCTCTATGCTGTGCTGGTCCA 1079 hDUB8.2 ATACATGTCTCAGCAGAACACAGGACCTCTTGTCTATGTCCTCTATGCTGTGCTGGTCCA 1076 _{************* **** **}*_{******* *****************************} hDUB4.5 CGCTGGGTGGAGTTGTCACAACGGACATTACTTCTCTTATGTCAAAGCTCAAGAAGGCCA 1139 hDUB4.8 CGCTGGGTGGAGTTGTCACAACGGACATTACTTCTCTTATGTCAAAGCTCAAGAAGGCCA 1139 hDUB8.2 CGCTGGGTGGAGTTGTCACAACGGACATTACTTATCTTATGTCAAA-CTCAAGAAGGCCA 1135 _{********************************* ************ *************} hDUB4.5 GTGGTATAAAATGGATGATGCCGAGGTCACCGCCTCTAGCATCACTTCTGTCCTGAGTCA 1199 hDUB4.8 ATGGTATAAAATGGATGATGCCGAGGTCACCGCCGCTAGCATCACTTCTGTCCTGAGTCA 1199 hDUB8.2 TTGGTATAAAATGGATGATGCCGAGGTCACTGCCTCCGGTATCACTTCTGTCCTGAGTCA 1195

_{***************************** *** * * ********************} hDUB4.5 ACAGGCCTACGTCCTCTTTTACATCCAGAAGAGTGAATGGGAAAGACACAGTGAGAGTGT 1259 hDUB4.8 ACAGGCCTACGTCCTCTTTTACATCCAGAAGAGTGAATGGGAAAGACACAGTGAGAGTGT 1259 hDUB8.2 ACAGGCCTATGTCCTCTTTTACATCCAGAAGAATGAATTTGGAAGACCCAGTTACAGTGT 1255 _{********* ********************** ***** * ***** **** * *****} hDUB4.5 GTCAAGAGGCAGGGAACCAAGAGCCCTTGGCGCAGAAGACACAGACAGGCGAGCAACGCA 1319 hDUB4.8 GTCAAGAGGCAGGGAACCAAGAGCCCTTGGCGCAGAAGACACAGACAGGCGAGCAACGCA 1319 hDUB8.2 GTCCATAGGCAGGGAACCAAGAGCTCTTTGCGTGAAGGCAAGTGAATTGTGTGTGAAATA 1315 _{*** * *********}*_{******** *** *** * * * ** * * * * *} hDUB4.5 AGGAGAGCTCAAGAGAGACCACCCCTGCCTCCAGGCCCCCGAGTTGGACGAGCACTTGGT 1379 hDUB4.8 AGGAGAGCTCAAGAGAGACCACCCCTGCCTCCAGGCCCCCGAGTTGGACGAGCACTTGGT 1379 hDUB8.2 AAATG TCATGA ATAAATCTTGCAGTGGAGTATTT-ATTTGTCTCACTTTGTAAT 1368

_{* * *** ** * * * *** * * *** * * *} hDUB4.5 GGAAAGAGCCACTCAGGAAAGCACCTTAGACCACTGGAAATTCCTTCAAGAGCAAAACAA 1439 hDUB4.8 GGAAAGAGCCACTCAGGAAAGCACCTTAGACCACTGGAAATTCCTTCAAGAGCAAAACAA 1439 hDUB8.2 CAGTGAATGAGCTTTAACCAATATCAATGCCTAGTGCCTACCCCCCAGAGATAAGAACTT 1428 _{* ** * * * * * * ** * ** *** * ***} hDUB4.5 AACGAAGCCTGAGTTCAACGTCAGAAAAGTCGAAGGTACCCTGCCTCCCGACGTACTTGT 1499 hDUB4.8 AACGAAGCCTGAGTTCAACGTCAGAAAAGTCGAAGGTACCCTGCCTCCCGACGTACTTGT 1499 hDUB8.2 CCACTCTCTTATGTGTAAC- -CATGGCCTCTGGATTGCTTATGACTCTGAAGATAATTCT 1486

_{* * ** *** ** * * ** *** * ** ** *} hDUB4.5 GATTCATCAATCAAAATACAAGTGTGGGATGAAGAACCATCATCCTG-AACAGCAAAGCT 1558 hDUB4.8 GATTCATCAATCAAAATACAAGTGTGGGATGAAGAACCATCATCCTG-AACAGCAAAGCT 1558 hDUB8.2 CCTT- -TCCCCCAACGTTTCAGAATCACTTCAGGTGGTGGTAACAGATAACACATCAGTC 1544

** ** *** * ** * * * * * * **** ** hDUB4.5 CCCTGCTAAACCTCTCTTCGACGACCCCGACACATCAGGAGTCCATGAACACTGGCACAC 1618 hDUB4.8 CCCTGCTAAACCTCTCTTCGTCGACCCCGACACATCAGGAGTCCATGAACACTGGCACAC 1618 hDUB8.2 CCTTTCTCTCTCTTTTCTCTTCACTCAGGAAAACTCTCACTGAGACAAAGGAAAATCCTA 1604

** * ** ** * ** * * ** * ** * ** * hDUB4.5 TCGCTTCCCTGCGAGGGAGGGC CAGGAGATCCAAAGGGAAGAACAAACACAGCAA 1673 hDUB4.8 TCGCTTCCCTGCGAGGGAGGGC CAGGAGATCCAAAGGGAAGAACAAACACAGCAA 1673 hDUB8.2 TGGTTTACTGGGGAGGAAGAATTCCCTCAGGAGTGAAATTGGTGGCTCCTTCCTCCCTGT 1664 _{* * ** * * **** ** ****** * ** * * *} hDUB4.5 GAGGGCTCTGCTTGTGTG CCAGTGGTCTCAGTGGAAGTACCGACCCACA 1722 hDUB4.8 GAGGGCTCTGCTTGTGTG CCAGTGA 1698 hDUB8.2 CAAGTCTCTTCCTCAGGATTGCCCCTTTGTCTCTTCAGGACT 1706

_{* * **** * * * ** *}

Table 26 Deduced amino acid alignment of hDUB4.5, hDUB4.8 and hDUB8.2 N-terminal potential mitochondrial targeting sequences are underlined. hDUB4.5 MRQRA HLKTLSEGIASFCNLRSQQKNLVILVPVDMEEDSLYLGGEWQFNHFSKLTSSRP 60 hDUB4.8 MRQRARHLKTLSEGIASCCKLRSQQKNLVILVPVDMEDDSLYLGGEWQFNHFSKLTSSRP 60 hDUB8.2 MRPESPSFED-SEEIASFCNLRSQPKNLVILVPGDMEDDSLYLGGEWQFNHFSKLTSSRP 59

** .. ** *** *.**** ******** ***.********************** hDUB4.5 DAAFAEIQRTSLPEKSPLSCETRVDLCDDI-APVARQI-APREKLPLSNRRPAAVGAGLQNM 120 hDUB4.8 DAAFAEIQRTSLPEKSPLSCETRVDLCDDLAPVARQLAPREKLPLSSRRPAAVGAGLQNM 120 hDUB8.2 DAAFAEIQRTSLSEKSSLSSETRVDLCDDI-APVARQLAPREKLPLSSRRPAAVGAGLQNM 119

_{************ *** ** ************************** *************} hDUB4.5 GNTCYVNASLQCLTYTPPLANYMLSREHSQTCHRHKGCMLCTMQAHITRALHNPGHVIQP 180 hDUB4.8 GNTCYVNASLQCLTYTPPLANYMLSREHSQTCHRHKGCMLCTMQAHITRALHNPGHVIQP 180 hDUB8.2 GNTCYVNASLQCLTYTPPLANYMLSREHSQTCHRHKCCMLCTMQAHITWPLHSPGHVIQP 179 ************************************ *********** ** ******* hDUB4.5 SQALAAGFHRGKQEDAHEFLMFTVDAMKKACLPGHKQVDHHSKDTT IHQIFGGYWRSQI 240 hDUB4.8 SQALAAGFHRGKQEDAHEFLMFTVDAMKKACLPGHKQVDHHSKDTTLIHQIFGGYWRSQI 240 hDUB8.2 SQVLAAGFHRGEQEDAHEFLMFTVDAMKKAFLPGHKHLDNHSKDTTLIHQIFGGYWRSHI 239 ** _ ******** . ****************** ***** _{: :} * . ****************** . * hDUB4.5 KCLHCHGISDTFDPYLDIALDIQAAQSVQQALEQLVKPEELNGENAYHCGVCLQRAPASK 300 hDUB4.8 KCLHCHGISDTFDPYLDIALDIQAAQSVQQALEQLVKPEELNGENAYHCGVCLQRAPASK 300 hDUB8.2 NCFHCHGISDTFDPYLDIALDIQAAQSVKQAL 271

. * . ************************* . *** hDUB4.5 TLTLHTSAKVLILVLKRFSDVTGNKIDKNVQYPECLDMKLYMSQTNSGPLVYVLYAVLVH 360 hDUB4.8 TLTLHTSAKVLILVLKRFSDVTGNKIAKNVQYPECLDMQPYMSQQNTGPLVYVLYAVLVH 360 hDUB8.2

hDUB4.5 AGWSCHNGHYFSYVKAQEGQWYKMDDAEVTASSITSVLSQQAYVLFYIQKSEWERHSESV 420 hDUB4.8 AGWSCHNGHYFSYVKAQEGQ YKMDDAEVTAASITSVLSQQAYVLFYIQKSEWERHSESV 420 hDUB8.2

hDUB4.5 SRGREPRALGAEDTDRRATQGELKRDHPCLQAPELDEHLVERATQESTLDHWKFLQEQNK 480 hDUB4.8 SRGREPRALGAEDTDRRATQGELKRDHPCLQAPELDEHLVERATQESTLDHWKFLQEQNK 480 hDUB8.2

hDUB4.5 TKPEFNVRKVEGTLPPDVLVIHQSKYKCGMKNHHPEQQSSLLNLSSTTPTHQESMNTGTL 540 hDUB4.8 TKPEFNVRKVEGTLPPDVLVIHQSKYKCGMKNHHPEQQSSLLNLSSSTPTHQESMNTGTL 540 hDUB8.2

hDUB4.5 ASLRGRARRSKGKNKHSKRALLVCQWSQ KYRPT 574 hDUB4.8 AS RGRARRSKGKNKHSKRALLVCQ 565 hDUB8.2

Table 27 Upstream of initiation codon nucleotide sequence (putative promoter region) alignment of hDUB4 5, hDUB4 8 and hDUB8 2

Numbering is initiated from initiation ATG hDUB4.5 CACACGAACACAATCACACACACACACTCACACGGTTTCCTACGTAAAGATTTCTTCCCT -276 hDUB4.8 CACACGAACACAATCACACACACACACTCACACGGTTTCCTACGTAAAGATTTCTTCCCT -276 hDUB8.2 GGGAGAAAAACACACACACACACACACACACACGGTTTCATAGGTAAAGATTTCTTCCCT -276 * ** *** ************* *********** ** ***************** hDUB4.5 GCCATTGCTTTACCTAAAATAAGGCAACTGTGTGGCCACTGTCCCAACCCGGTTACACTC -216 hDUB4.8 GCCATTGCTTTACCTAAAATAAGGCAACTGTGTGGCCACTGTCCCAACCCGGTTACACTC -216 hDUB8.2 GACATTGTTTTACCTAAAATAAGGCAACTGTGTGGCCACTGTCCCAACCCGGTTACACTC - 216 * ***** **************************************************** hDUB4.5 CTATTATATGTGCCTATCATCCTGAGGAGTAATTTGATTCAGGTGTTCTGGAAGTCATGC - 156 hDUB4.8 CTATTATATGTGCCTATCATCCTGAGGAGTAATTTGATTCAGGTGTTCTGGAAGTCATGC - 156 hDUB8.2 ATATTACATGTGTCTATCAGCCTGAGGAGTAGTTTGATTCAGGTGTTCTAGAAGTCATGA - 156 ***** ***** ****** *********** ***************** ********* hDUB4.5 TGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCAAGGGGACACACCCTGTGACTCCTTCC - 96 hDUB4.8 TGTGGGCTGTGTCTGTTGAATACCCAGCGATGCAAGGGGACACACCCTGTGACTCCTTCC -96 hDUB8.2 TGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCAAGGGGACACACCCTGTGACTCATTCC -96 ********************* ********************************* **** hDUB4.5 TGAATTGAGTGCTGATATTTGATTGGCTTATCGCGCACCTGATGAGTGGGTGGGGTGTTC -36 hDUB4.8 TGAATTGAGTGCTGATATTTGATTGGCTTATCGCGCACCTGATGAGTGGGTGGGGTGTTC -36 hDUB8.2 TTAATTGAGTGCTGATATTTGATTGGTTTATCGCGCACCTGATGGGTGGGTGGGGTGTTC -36

* ************************ ***************** *************** hDUB4.5 GCGGTTGGTGGGGTTGACTTACAGAAGGGCTGATG 0 hDUB4.8 GCGGTTGGTGGGGGTGACTTACAGAAGGGCTGATG 0 hDUB8.2 GCGGTTGGTGGGGGTGAGTTATATAAGGGCTGATG 0 ************* *** *** * ***********

Table 28 CLUSTAL W (1.81) multiple sequence alignment of core amino acids of hDUBs

8.5 MEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLSSEARVDLCDDLAPVAR 60

8.7 MEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLSSEARVDLCDDLAPVAR 60 8.1 MGDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLSSETRVDLCDDLAPVAR 60

4.2 MEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLSCETRVDLCDDLAPVAR 60

4.3 MEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLSCETRVDLCDDLAPVAR 60

4.5 MEEDSLYLGGE QFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLSCETRVDLCDDLAPVAR 60 4.1 MEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTS PEKSPLSCETRVDLCDDLAPVAR 60 8.3 MEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSQLSTETRVDFCDDLAPVAR 60

8.11 MEDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSQLSTETRVDFCDDI-AAVAR 60

8.8 MEDDSLYLGGDWQFNHFSKLTSSRLDAAFAEIQRTSLSEKSPLSSETRFDLCDDLAPVAR 60

8.6 MEDDSLYLGGDWQFNHFSKLTSSRLDAAFAEIQRTSLSEKSPLSSETRFDLCDDLAPVAR 60 * .*******.************* ************ _# *** ** *.* *.***** ***

8.5 QLAPRKKLPLSSRRPAAVGAGLQNMGNTCYENASLQCLTYTPPLANYMLSREHSQTCQRP 120

8.7 QLAPRKKLPLSSRRPAAVGAGLQNMGNTCYENASLQCLTYTPPLANYMLSREHSQTCQRP 120

8.1 QLAPREKLPLSSRRPAAVGAGLQNMGNTCYENASLQCLTYTLPI-ANYMLSREHSQTCQRP 120

4.2 QLAPREKLPLSSRRPAAVGAGLQNMGNTCYVNASLQCLTYTTPI-ANYMLSREHSQTCHRH 120 4.3 QLAPREKLPLSSRRPAAVGAGLQNMGNTCYVNASLQCLTYTPPLANYMLSREHSQTCHRH 120

4.5 QLAPREKLPLSNRRPAAVGAGLQNMGNTCYV ASLQCLTYTPPLANYMLSREHSQTCHRH 120 4.1 QLAPREKPPLSSRRPAAVGAGLQNMGNTCYV ASLQCLTYKPPLANYMLFREHSQTCHRH 120

8.3 QLAPREKLPLSSRRPAAVGAGLQNMGNTCYVNASQQCLTYTPPLANYMLSREHSQTCHRH 120 8.11 QLAPREKLPLSSRRPAAVGAGLQNMGNTCYV ASQQCLTYIPPLA YMLSREHSQTCHRH 120 8.8 QLAPREKLPLSSRRPAAVGAGLQKIGNTFYVNVSLQCLTYTLPLSNYMLSREDSQTCHLH 120

8.6 QLAPREKLPLSSRRPAAVGAGLQKIGNTFYVNVSLQCLTYTLPLSNYMLSREDSQTCHLH 120 *****.* ***_^***********..*** * *.* ***** **.**** * * **** .

8.5 KCCMLCTMQAHITWALHSPGHVIQPSQALAAGFHRGKQEDAHEFLMFTVDAMKKACLPGH 180 8.7 KCCMLCTMQAHITWALHSPGHVIQPSQALAAGFHRGKQEDAHEFLMFTVDAMKKACLPGH 180

8.1 KCCMLCTMQAHITWALHSPGHVIQPSQALAAGFHRGKQEDVHEFLMFTVDAMKKACLPGH 180

4.2 KGCMLCTMQAHITRALHNPGHVIQPSQALAAGFHRGKQEDAHEFLMFTVDAMKKACLPGH 180

4.3 KGCMLCTMQAHITRALHNPGHVIQPSQALAAGFHRGKQEDAHEFLMFTVDAMKKACLPGH 180

4.5 KGCMLCTMQAHITRALHNPGHVIQPSQALAAGFHRGKQEDAHEFLMFTVDAMKKACLPGH 180 4.1 KGCMLCTMQAHITRALHIPGHVIQPSQALAAGFHRGKQEDAHEFLMFTVDAMRKACLPGH 180

8.3 KCCMLCTMEAHITWPLHIPGHVIQPSQALAAGFHRGKQEAALEFLMFTVDAMKKACLPGH 180

8.11 KCCMLCTMEAHITWPLHIPGHVIQPSQALAAGFHRGKQEAALEFLMFTVDAMKKACLPGH 180

8.8 KCCMFCTMQAHITWALYRPGHVIQPSQVLAAGFHRGEQEDAHEFLMFTVDAMKKACLPGH 180

8.6 KCCMFCTMQAHITWALYRPGHVIQPSQVLAAGFHRGEQEDAHEFLMFTVDAMKKACLPGH 180 _{* **};_***;_{**** (*}; _{********* # ********}; _{** t **********};*_******

8.5 KQVDHHSKDTTLIHQIFGGCWRSQIKCLHCHGISDTFDPYLDIALDIQAAQSVKQALEQL 240

8.7 KQVDHHSKDTTLIHQIFGGCWRSQIKCLHCHGISDTFDPYLDIALDIQAAQSVKQALEQL 240 8.1 KQVDHHCKDTTLIHQIFGGCWRSQIKCLHCHGISDTFDPYLDIALDIQAAQSVKQALEQL 240 4.2 KQVDHHSKDTTLIHQIFGGYWRSQIKCLHCHGISDTFDPYLDIALDIQAAQSVQQALEQL 240

4.3 KQVDHHSKDTTLIHQIFGGYWRSQIKCLHCHGISDTFDPYLDIALDIQAAQSVQQALEQL 240

4.5 KQVDHHSKDTTLIHQIFGGYWRSQIKCLHCHGISDTFDPYLDIALDIQAAQSVQQALEQL 240

4.1 KQVDRHSKDTTLIHQIFGGYWRSQIKCLHCHGISDTFDPYLDIALDIQAAQSVQQALEQL 240

8.3 KQVDHHSKDTTLIHQIFGGYWRSQIKCLHCHGISDTFGPYLDIALDIQEAQSVKQALEQL 240 8.11 K QILILVWKRFSDVTG 196

8.8 KQLDHHSKDTTLIHQIFGAYWRSQIKYLHCHGISDTFDPYLDIALDIQAAQSVKQALEQL 240

8.6 KQLDHHSKDTTLIHQIFGAYWRSQIKYLHCHGISDTFDPYLDIALDIQAAQSVKQALEQL 240 8.5 VKPEELNGENAYHCGLCLQRAPVSKTLTLHTFAKERILETQRPWWTRHKLAKSVQYAES 300

8.7 VKPEELNGENAYHCGLCLQRAPASKTLTLHTSAKVLILVLKRFSDVTGNKLAKNVQYPEC 300 8.1 VKPEELNGENAYHCGLCLQRAPASNTLTLHTSAKVLILVLKRFSDVAGNKLAK-MVQYPEC 300 4.2 VKPEELNGENAYHSGVCLQRAPASKTLTLHTSAKVLILVLKRFSDVTGNKIAKNVQYPEC 300

4.3 VKPEELNGENAYHCGVCLQRAPASKTLTLHTSAKVLILVLKRFSDVTGNKIAKNVQYPEC 300

4.5 VKPEELNGENAYHCGVCLQRAPASKTLTLHTSAKVLILVLKRFSDVTGNKIDKNVQYPEC 300 4.1 VKPEELNGENAYHCGVCLQRAPASKTLTLHNSAKVLILVLKRFPDVTGNKIAKNVQYPEC 300 8.3 VKPEELNGENAYHC GNKIAKNVQYPEC 267 8.11 NKIAKNVQYPEC 208

8.8 VKPKELNGENAYHCGLCLQKAPASKTLTLPTSAKVLILVLKRFSDVTGNKLAKNVQYPKC 300

8.6 VKPKELNGENAYHCGLCLQKAPASKTLTLPTSAKVLILVLKRFSDVTGNKLAKJMVQYPKC 300

_: * . *_*** ._ 8.5 LDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHDGHYFSYVKAQEGQWYKMDDAKVTACSIT 360

8.7 LDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHDGHYFSYVKAQEGQWYKMDDAKVTACSIT 360

8.1 LDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHDGHYFSYVKAQEVQWYKMDDAEVTVCSII 360

4.2 LDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHNGHYFSYVKAQEGQWYKMDDAEVTAASIT 360

4.3 LDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHNGHYFSYVKAQEGQWYKMDDAEVTAASIT 360 4.5 LDMKLYMSQTNSGPLVYVLYAVLVHAGWSCHNGHYFSYVKAQEGQWYKMDDAEVTASSIT 360

4.1 LDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHNGHYSSYVKAQEGQWYKMDDAEVTASSIT 360 8.3 LDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHNGHYFSYVKVQEGQWYKMDDAEVTASGIT 327 8.11 LDMQPYMSQQNTGPLVYVLYAVLVHAG SCHNGHYFSYVKVQEGQWYKMDDAE 261

8.8 RDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHNGHYFSYVKAQEGQWYKMDDAEVTASGIT 360 8.6 RDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHNGHYFSYVKAQEGQWYKMDDAEVTASGIT 360

**. **** *.*******************.*** **** ** ********.

8.5 SVLSQQAYVLFYIQKSE ERHSESVSRGREPRALGAEDTDRRATQGELKRDHPCLQAPEL 420

8.7 SVLSQQAYVLFYIQKSEWERHSESVSRGREPRALGAEDTDRRATQGELKRDHPCLQAPEL 420 8.1 SVLSQQAYVLFYIQKSEWERHSESVSRGREPRALGAEDTDRRAKQGELKRDHPCLQAPEL 420

4.2 SA SQQAYVLFYIQKSEWERHSESVSRGREPRALGTEDTDRRATQGELKRDHPCLQAPEL 420

4.3 SVLSQQAYVLFYIQKSEWERHSESVSRGREPRALGAEDTDRRATQGELKRDHPCLQAPEL 420

4.5 SVLSQQAYVLFYIQKSEWERHSESVSRGREPRALGAEDTDRRATQGELKRDHPCLQAPEL 420 4.1 SVLSQQAYVLFYIQKSEWERHSESVSRGREPRALGVEDTDRRATQGELKRDHPCLQAPEL 420 8.3 SVLSQQAYVLFYIHKSEWERHSESVSRGREPRALGAEDTDRRATQGELKRDYPCLQVPEL 387

8.11 KSEWERHSESVSRGREPRALGAEDTDRRATQGELKRDYPCLQVPEL 307

8.8 SVLSQQAYVLFYIQKSEWERHSESVSRGREPRALGAEDTDRPATQGELKRDHPCLQVPEL 420

8.6 SVLSQQAYVLFYIQKSEWERHSESVSRGREPRALGAEDTDRPATQGELKRDHPCLQVPEL 420

********************* _# ***** * _ ******* . **** _f ***

8.5 DERLVERATQESTLDHWRFPQEQNKTKPEFNVRKVEGTLPPNVLVIHQSKYKCGMKNHHP 480

8.7 DERLVERATQESTLDHWRFPQEQNKTKPEFNVRKVEGTLPPNVLVIHQSKYKCGMKNHHP 480

8.1 DEHLVERATQESTLDH KFLQEQNKTKPEFNVGKVEGTLPPNALVIHQSKYKCGMKNHHP 480

4.2 DEHLVERATQESTLDHWKFLQEQNKTKPEF VRKVEGTLPPDVLVIHQSKYKCGMKNHHP 480 4.3 DEHLVERATQESTLDR KFLQEQNKTKPEF VRKVEGTLPPDVLVIHQSKYKCGMKNHHP 480

4.5 DEHLVERATQEΞTLDHWKFLQEQNKTKPEFNVRKVEGTLPPDVLVIHQSKYKCGMKNHHP 480 4.1 DEHLVERATQESTLDHWKFLQEQNKTKPEFNVRRVEGTVPPDVLVIHQSKYKCRMKNHHP 480

8.3 DEHLVERATQESTLDHWKFLQEQNKTKPEFNVRKLEGTLPPNVLVIHQSKYKCG KNHHP 447 8.11 DEHLVERATQESTLDH KFLQEQNKTKPEFNVRKLEGTLPPNVLVIHQSKYKCGMK HHP 367 8.8- DEHLVERATQESTLDHWKFPQKQNKTKPEFNVRKVEGTLPPNVLVIHQSKYKCGMKNHHP 480

8.6 DEHLVERATQESTLDHWKFPQKQNKTKPEFNVRKVEGTLPPNVLVIHQSKYKCGMKNHHP 480 **.************•*.* *.********** ..***.**. ********** ****** 8.5 EQQSSLLNLSSTTRTDQESV TGTLASLQGRTRRSKGKNKHSKRALLVCQ 530

8.7 EQQSSLLNLSSTTRTDQESVNTGTLASLQGRTRRSKGKNKHSKRALLVCQ 530 8.1 EQQSSLLNLSSTTRTDQESMNTGTLASLQGRTRRAKGKNKHSKRALLVCQ 530 4.2 EQQSSLLNLSSSTPTHQESMNTGTLASLRGRARRSKGKNKHSKRALLVCQ 530

4.3 EQQSSLLNLSSSTPTHQESM TGTLASLRGRARRSKGKNKHSKRALLVCQ 530

4.5 EQQSSLLNLSSTTPTHQESM TGTLASLRGRARRSKGKNKHSKRALLVCQ 530 4.1 EQQSSLLNLSSTTPTDQESM TGTLASLRGRTRRSKGKNKHSKRALLVCQ 530 8.3 EQQSSLLNLSSTNPTDQESMNTGTLASLQGRTRRAKGKNKHCKRALLVCQ 497 8.11 EQQSSLLNLSSTNPTDQESMNTGTLASLQGRTRRSKGKNKHCKRALLVCQ 417

8.8 EQQSSVLNLSSTKPTDQESM TGTLASLQGSTRRSKGNNKHSKRSLLVCQ 530

8.6 EQQSSLLNLSSTKPTDQESMNTGTLASLQGSTRRSKGNNKHSKRSLLVCQ 530 *****.*****. * ***.********.* .**.**.*** **.*****

Table 29 CLUSTAL W (1.81) multiple sequence alignment of putative promoter sequences of hDUBs (upstream of ATG initiation codon)

8.9 TGACGTGTGTGAAAACTACAGTGTGATGAGCATGACTTGCAGACAGGTTATCGATTGGGC 60 8.10 -GACGTGTGTGAAAACTACAGTGTGACGAGCATGACTCGCAGACAGGTTATCGATTGGGC 59

8.3 GATATCAATACGGC 14

8.11 GATATCAATACGGC 14

4.2_a TTATCGATTGGGC 13

4.5 TGAGCATGACTGGCAGACAGCTTATCGATTGGGC 34 4.3 GATGAGCATGACTGGCAGACAGCTTATCGATTGGGC 36

4.2_b GTGATGAGCATGACTGGCAGACAGCTTATCGATTGGGC 38

4.4 GTGATGAGCATGACTGGCAGACAGCTTATCGATTGGGC 38

4. l_b AGTGCAATGAGCATGACACGCAGGCAGGATATCAATTCGGC 41

8.1 CAATGAGCATGACACGAAGACAGAATATCAATTCGGC 37 8.7 CAATGAGCATGACATGCAGGCAGGACATCAATTCGGC 37

8.6 TGTGATGAGCATGACTCGCAGACAGGTTATCGATTGGGC 39

8.8 TGTGATGAGCATGACTCGCAGACAGGTTATCGATTGGGC 39

8.5 TCTCTGTCAGAACCATGGTACTCTGTTGTGGTGTGAAAGTAGC 43

8.2 TCACATCTTCTCGGCCAGATGCAGCCTTTGCTGAAATCCAGCGGACTTCTC 51 4.1_a AGTATAGCAGAGCAGAGAGCTG-GAAGGGACC 31

* *

8.9 T-CCCCTCAAAAT-TAGTTATGAGCATTAAAGGACACCGATGCCC AGGTCCCGGCTG 115

8.10 T- CCCCTCAAAAT- CAGTTATGAGCATTAAAGCACACCGATGCCC AGGTCCCGGCTC 114 8.3 T-CACCTCAAAAG-CAGTTATGAGCATTAAAGGACACCCATGCCT AGGTCCCGCTTA 69

8.11 T-CACCTCAAAAG-CAGTTATGAGCATTAAAGGACACCCATGCCT AGGTCCCGGTTA 69

4.2_a T-CCCCTCAAAAT-CGGTTATGAGCATTCAAGCACACCGATGCCC AGGTCCCGGCTG 68

4.5 T-CCCCTCAAAAT-CGGTTATGAGCATTCAAGCACACCGATGCCC AGGTCCCGGCTG 89

4.3 T-CCCCTCAAAAT-CGGTTATGAGCATTCAAGCACACCGATGCCC AGGTCCCGGCTG 91 4.2_b T- CCCCTCAAAAT- CGGTTATGAGCATTCAAGCACACCGATGCCC AGGTCCCGGCTG 93

4.4 T- CCCCTCAAAAT-CGGTTATGAGTATTCAAGCACACCGATGCCC AGGTCCCGGCTG 93

4.1_b T-CCCCTCAAAAG-CTGTTATGAGCATTAAAGGACACCAATGCCT AGTTCCCGGTTA 96

8.1 T-CACCTCAAAT--CAGTTGTGAGCATTAAAGAAAACCAATTCCT AGGTCCCGCTTA 91

8.7 T- CACCTCAAAAG- CAGTTATGAGCATTAAAGGACAACAATTCCT AGGTCCCGCTTA 92 8.6 T-CCCCTCAAAAT-CAGTTAGGAACATGAAAGCACACCGATGCCC AGGTCCTGGCTG 94

8.8 T-CCCCTCAAAAT-CAGTTAGGAACATGAAAGCACACCGATGCCC AGGTCCTGGCTG 94

8.5 CACAGATCATCTG-TAGAT-TAAGGGGTGTGGCTTTGTTCCAACA AAGCTTTATTTA 98

8.2 TCCCTGAGAAGTCACAACTCTCAACTGAGACCCGCGTCGACTTCTGCGATGATTTGGCGC 111

4. l_a TGCATCCCTAAT GATATAAGAAAGTATCTGTACTAGCCCTGA- -ATGGTATAACTA 85 * * * *

8.9 CAGGAATAAGAC-CCTCCGACGTCTTGTGTGAAGCCACGGC- -ATCTGGATTGCTCATGC 172

8.10 CAGGAATAAGAC-CCTCCAGCGTCTTGTGTGAAGCCACGGC--ATGTGGATTGCTCATGC 171

8.3 AAGAGATAAGAC-TCTCCCACACCCTGTGTGAAGCCACGGC- -ATGTGGATTGCTCATGC 126 8.11 AAGAGATAAGAC-TCTCCCACACCCTGTGTGAAGCCACGGC- -ATGTGGATTGCTCATGC 126

4.2_a CAGGAATAAGAC-CCTCCAGGGTCTTGTGTGAAGCCTCGGC--ATCTGCATTGCTCATGC 125

4.5 CAGGAATAAGAC-CCTCCAGGGTCTTGTGTGAAGCCTCGGC--ATCTGCATTGCTCATGC 146

4.3 CAGGAATAAGAC-CCTCCAGGGTCTTGTGTGAAGCCTCGGC- -ATCTGCATTGCTCATGC 148

4.2_b CAGGAATAAGAC-CCTCCAGGGTCTTGTGTGAAGCCTCGGC- -ATCTGCATTGCTCATGC 150 4.4 CAGGAATAAGAC-CCTCCAGGGTCTTGTGTGAAGCCTCGGC- -ATCTGCATTGCTCATGC 150

4. l_b AAACGATAAGAC-TCTCGCACACCCTGTGGGAAGCCACGGC- -ATCTGGATTGCTCATGC 153

8.1 AAGAGATAAGAC-CATCCAACAACCTGTGTGAAGCCACCGC--ATCTGGCTTGCTCATGA 148 8.7 AAGAGATAAGAC-CATCCAACACCCTGTGTGAAGCCACGGC- -ATCTGGATTGCTCATGT 149

8.6 CAGGAATAAGAT-CCTCCGACGTCTTGTGTGAAGCCACGAC- -ATCTGCATTGCTCATGC 151 8.8 CAGGAATAAGAT-CCTCCGACGTCTTGTGTGAAGCCACGAC- -ATCTGCATTGCTCATGC 151

8.5 CAAACACAGGCTGTGGGCTGGATTTGGCCTGCAGCTGTAGT- -TTGTG ATCCTTGA 152

8.2 CTGTGGCAAGAC- -AGCTTGCTCCCAGGGAGAAGCTTCCTCTGAGTAGCAGGAGACCTGC 169 4. l_a CAG-GTTAAATT TACGTGAAAAAGAAATCAACTTCTGCCTTGTTTAAGCAAACTTA- 140

* * * * * * 8 . 9 TTCTG-G-GGATCATTCTCCTGAAAATG- -GTGGCTCCTTCCTGCCTGTGGAGCACCTCT 228

8 . 10 TTCTG-G-GGATCATTCTCCTGAAAACG- -GTGGCTCCTTTCTCCCTGTGGAGCACCTTT 227

8 . 3 TTCTG-G-GGATCATTCTCCTGAAAATG- -GTGGCTCCTTTCTCACTGTGGAGCATCTTT 182

8 - 11 TTCTG-G-GGATCATTCTCCTGAAAATG- -GTGGCTCCTTTCTCACTGTGGAGCATCTTT 182

4 . 2_a TTCTG-G-GGATCATTCTCCTGAAAATG- -GTGGCTCCTTTCTCCCTGTGGAGCATCTTT 181

4 . 5 TTCTG-G-GGATCATTCTCCTGAAAATG- -GTGGCTCCTTTCTCCCTGTGGAGCATCTTT 202

4 . 3 TTCTG-G-GGATCATTCTCCTGAAAATG- -GTGGCTCCTTTCTCCCTGTGGAGCATCTTT 204

4 . 2_b TTCTG-G-GGATCATTCTCCTGAAAATG- -GTGGCTCCTTTCTCCCTGTGGAGCATCTTT 206 4 . 4 TTCTG-G-GGATCATTCTCCTGAAAATG- -GTGGCTCCTTTCTCCCTGTGGAGCATCTTT 206 4 4. .1l_bb TTCTG-G-GGATCATTTTCCTGAAAATC--GTGGCTGCTTTCTCCCTGTGTAGCATCTTT 209 8 . 1 TTCTG-G-GGATCATTCTCCAGAAAATG- -GTGGCTCCTTTCTCCCTGTGGAGCATCTTT 204

8 . 7 TTCTG-G-GGAACATTCTTCTGAAAATG- -GCGGCTCCTTTCTCCCTGTGGAGCATCTTT 205

8 . 6 TTCTG-G-GGATCATTCTCCTGAAAATG- -GTGGCTTCTTTCTCCCTGTGGAGCATCTTT 207

8 . 8 TTCTG-G-GGATCATTCTCCTGAAAATG- -GTGGCTTCTTTCTCCCTGTGGAGCATCTTT 207 8 8. .55 TTCAG-ACAGTTTAGCAAGGCTGAAAAG--AACACCCACACCCCCTTGTTACCCACAGAT 209

8 . 2 TGCGGTGGGGGCTGGGCTCCAGAATATG- -GGAAATACCTGCTACGTG AACGCTTCC 224

4 . l_a TTCAG GCATTAATTTTATAAATATGTAGAGAATACATACTCCTTAT-GAGCAGA 193

* * * * * * * * 8 8. .99 CTA-AGCA-GTGC-CCTTTCTTCACCCAGGACACTTTACATCAGGCACAGAAAGCCTTCT 285

8 . 10 CTA-AGCA-GTGC-CCTTTCTTCACCCAGGACACTTTACATCAGGCACAGAAAGCCTTCT 284

8 . 3 GTA-AGCA-GTGT-CCTTTCTTCCCCCAGGACACTTTACTTCAGGCACAGGAAGCCTTCT 239

8 . 11 CTA-AGCA-GTGT-CCTTTCTTCCCCCAGGACACTTTACTTCAGGCACAGGAAGCCTTCT 239

4 . 2_a CTA-AGCA-GTGCTCTTTTCTTCCCCCAGGACACTTTACATCCGGCACAGGAAGCCTTCT 239 44..55 CTA-AGCA-GTGCTCTTTTCTTCCCCCAGGACACTTTACATCCGGCACAGGAAGCCTTCT 260

4 . 3 CTA-AGCA-GTGCTCTTTTCTTCCCCCAGGACACTTTACATCCGGCACAGGAAGCCTTCT 262

4 . 2_b CTA-AGCA-GTGCTCTTTTCTTCCCCCAGGACACTTTACATCCGGCACAGGAAGCCTTCT 264 4 . 4 CTA-AGCA-GTGCTCTTTTCTTCCCCCAGGACACTTTACATCCGGCACAGGAAGCCTTCT 264

4 , . l_b CTA-AGCA-GTGCTCCTTTCTTCCCACAGGAAACTTTACATCAGGCACAGGAAGCTTTCT 267 88...11 CTA-AGCA-GTGC-CCTTTCTTCCCCCAGGACACTTTACATGAGGTGCAGGAAGCCTTCT 261

8 . . 7 CTA-AGCA-GTGCTCCTTTCTTCCCCCAGGACACTTTACATCAGGCATAGGAAGCCTTCT 263

8 . . 6 CTA-AGCA-GTGCTCCTTTCTTCCCCCAGGACACTTTACATCAGGCGCACGAAGCCTTCT 265

8 . . 8 CTA-AGCA-GTGCTCCTTTCTTCCCCCAGGACACTTTACATCAGGCGCACGAAGCCTTCT 265

8 . . 5 GGGTGGGA-CTGTGTTGGCCAGAGACCGAGAGACGGGTGCTCACAGGGGAACGTACAGCA 268 8 8.. .22 CAGCAGTGTCTGACATACACACCGCCCCTTGCCAACTACATGCTGTCCCGGGAGCACTCT 284

4 . , l_a -AACAATGTTTGCGCCATATGGTCCATGATGGGTGTTCAATAATGTGTGATGATGATAAT 252 ** *

8 . . 9 GATGGAGCACACCTGGCCCATGAAAAGACAAGGGATAAGAAACGGGGCCAAACATCACAG 345 8 8.. .1100 GATGGAGCACACCTGGCCCATGAAAAAACAAGGGA-AAGAAACGGGGCCAAAGGTCACAG 343

8 . , 3 GATGGAGCACACCTGGCCCATGAAAAGACAAGGGA-AAGAAATGGGGCCAAAGGTCACAG 298

8 . 11 GATGGAGCACACCTGGCCCATGAAAAGACAAGGGA-AAGAAATGGGGCCAAAGGTCACAG 298

4 . 2_a GATGGAGCACACCTGGCCCATGAAAAGACAAGGGA-AAGAAACGGGGCCAAAGGTCACAG 298 4 .. 5 GATGGAGCACACCTGGCCCATGAAAAGACAAGGGA-AAGAAACGGGGCCAAAGGTCACAG 319 4 4.. .33 GATGGAGCACACCTGGCCCATGAAAAGACAAGGGA-AAGAAACGGGGCCAAAGGTCACAG 321

4 . 2_b GATGGAGCACACCTGGCCCATGAAAAGACAAGGGA-AAGAAACGGGGCCAAAGGTCACAG 323 4 . . 4 GATGGAGCACACCTGGCCCATGAAAAGACAAGGGA-AAGAAACGGGGCCAAAGGTCACAG 323

4 . , l_b GATGGAGCACACCTGGCCCATGAAAAGACAAGGGA-AAGAAATGGGGCCAAAGGTCACAG 326 8 . 1 GATGGAGCACACCTGGCCCATGAAAAGACAAGGGA-AAGAAAAAGGGCCAAAGGTCACAG 320 8 8..7 7 GATGAAGTACACCTGGCCCATGAAAAGACAAAGGA-AAGAAACAGGGCCAAAGGTCACAG 322

8 . 6 GATGGAGCACACCTGGCCCATGAAAAGACAAGGGA-AAGAAACGGGGCCAAAGGTCACAG 324

8 . 8 GATGGAGCACACCTGGCCCATGAAAAGACAAGGGA-AAGAAACGGGGCCAAAGGTCACAG 324

8 . . 5 TGTAGAGGCCGGAAGGTGCTCCAGGGCACAAGTGT-GGGAAAGTGGGACATACGGGGAAG 327

8 . . 2 CAAACATGTCATC- -GTCACAAGTGCTGCATGCTCTGTACCATGGAAGCTCACATCACAT 342 4 4.. ,11 aa AATGAAGACAATAGTGACAAATAAAAGAAAATAAA-AAGCAGTGAAACAAAGTGGTTTAA 311 8.9 TCCTCTCATTCCACCGTCCTCCTTAAAATCATCCTAATTTCATGGGCTCT-GCGGCCACG 404

8.10 TCCTCTCATTCCATCATCCTCCTTAAAATCATCCTAATTTCATGGGCCCT-GAGGCCACG 402 8.3 TCCTCTCATTCCATCATCCTCCTTAAAATCATCCTAATTTCATGGGCCCT-GAAGCCAGG 357

8.11 TCCTCTCATTCCATCATCCTCCTTAAAATCATCCTAATTTCATGGGCCCT-GAGGCCACG 357 4.2_a TCCTCTCATCCCATCATCCTCCTTAAAATCATCCTAATTTCATGGGCCCT-GAAGCCAGG 357

4.5 TCCTCTCATCCCATCATCCTCCTTAAAATCATCCTAATTTCATGGGCCCT-GAAGCCAGG 378

4.3 TCCTCTCATCCCATCATCCTCCTTAAAATCATCCTAATTTCATGGGCCCT-GAAGCCAGG 380 4.2_b TCCTCTCATCCCATCATCCTCCTTAAAATCATCCTAATTTCATGGGCCCT-GAAGCCAGG 382

4.4 TCCTCTCATCCCATCATCCTCCTTAAAATCATCCTAATTTCATGGGCCCT-GAAGCCAGG 382 4.1_b TCCTCTCATTCCATCATACTCCTTAAAATCATCCTAATTTCATGGGTCCT-GAAGCCAGG 385

8.1 TCCTCTCATTACATCATCATCCTTAAAATCATCCTAATTTCATGAGCCCT-GAAGACAGG 379

8.7 CCCACTCATTTCATCACCATCCTTAAAATCATCCTAATTTCATGGGCCAT-GAAGCCAGG 381

8.6 TCCTCTCATTCCATCATCCTCCTTAAAATCATCCGAATTTCATGAGCCCTTGAAGCCAGG 384

8.8 TCCTCTCATTCCATCATCCTCCTTAAAATCATCCGAATTTCATGAGCCCTTGAAGCCAGG 384 8.5 TTTCCAGAAAGCATGATGTCAAGTTGGAG-GTGGAGCGCTGCTGGGCTTGTGAAGGGTCT 386

8.2 GGCCCC TCCA-CATTCCTGGCCATGTCATCCAGCCCTCACAGGCATT G 389

4. l_a TAGCTATACATAGTTATT-TTGTTGAAAGATTCTGCTGCTAATATTATTCAATATTTTTG 370

* * 8.9 GCTGTTTCTTTACACCTCGAGACCTTGGCGCCAGGCCTCAATTCTGCCCCGGTGCTTACT 464

8.10 GCTGTTTCTTTACACCTCGAGACCTTGGCGCCGGGCCTCAATTCTGCTCCAGTGCTTACT 462

8.3 GCTGTTTCTTTAAAACTAGAGGCCTTGGCGCCGTGCCTCAATTCTGCCCTGTTCCTTACT 417

8.11 GCTGTTTCTTTAAAACTAGAGGCCTTGGCGCCGGGCCTCAATTTTGCCCTGTTCCTTACT 417

4.2_a GCTGTTTCTTTACACCTAGAGGCCTTGGCGCCGGGCCTCAATTCCGCCCTGTTCCTTACC 417 4.5 GCTGTTTCTTTACACCTAGAGGCCTTGGCGCCGGGCCTCAATTCCGCCCTGTTCCTTACC 438

4.3 GCTGTTTCTTTACACCTAGAGGCCTTGGCGCCGGGCCTCAATTCCGCCCTGTTCCTTACC 440

4.2_b GCTGTTTCTTTACACCTAGAGGCCTTGGCGCCGGGCCTCAATTCCGCCCTGTTCCTTACC 442

4.4 GCTGTTTCTTTACACCTAGAGGCCTTGGCGCCGGGCCTCAATTCCGCCCTGTTCCTTACC 442

4. l_b GCTGTTTCTTTACACCTAGAGGCCTTGGCGCCGGGCCTCAATTCTGCCCTGTTGCTTACT 445 8.1 GCTGTTTCTTTACACCTAGAGGCCTTGGCGCCGGGCCTCAATTCTGCCCTGTTCCTTACT 439

8.7 GCTGTTTCTTTACACCCAGAGGCCTTGGCGCCGGGCCTCAATTCTGCCCTGTTCCTTACT 441 8.6 GCTGTTTCTTTACACCCAGAGGCCTTGGCGCCGGGCCTCAATTCTGCCCTGTTCCTTACT 444 8.8 GCTGTTTCTTTACACCCAGAGGCCTTGGCGCCGGGCCTCAATTCTGCCCTGTTCCTTACT 444

8.5 CGAGTCCAAGTGAGGGCGGGTTGTGAAGGGTCTCCTCTCAAAGCTGACCGACTTCGGGAC 446 8.2 GCTGCTGGCTTCCATAGAGGCAAGCAGGAAGCTGCCCTTGAATTTCTCATGTTCACTGTG 449

4. l_a TATGCTGGC- -GCAAATAAGGAAATTTACATCGTCTAATAAAAATTATTTATCAATTTAT 428 * * *

8.9 GTCTAAGACATTTTGGGAAAATCCCTAGAGC-CTGGATCTTCAATCCTGGTAAGCCAGAG 523 8.10' " GTCTAAGACATTTTGGGAGAATCCCTAGAGC-CTAGATCTTCAATCCTGGTAAGCCAGAG 521

8.3 GTCTAAGAAAGGTTGGGAAAATCCCTAGAGC-CAGGATCTTCATTCCTGGTAAGCCAGAG 476 8.11 GTCTAAGAAAGGTTGGGAAAATCCCTAGAGC-CAGGATCTTCATTCCTGGTAAGCCAGAG 476 4.2_a GTCTAAGACATGTTGGGAAAATCCCTAGAGC-CAGGATCTTCATTCCTGCTAAGCCAGAC 476 4.5 GTCTAAGACATGTTGGGAAAATCCCTAGAGC-CAGGATCTTCATTCCTGCTAAGCCAGAC 497 4.3 GTCTAAGACATGTTGGGAAAATCCCTAGAGC-CAGGATCTTCATTCCTGCTAAGCCAGAC 499

4.2_b GTCTAAGACATGTTGGGAAAATCCCTAGAGC-CAGGATCTTCATTCCTGCTAAGCCAGAC 501

4.4 GTCTAAGACATGTTGGGAAAATCCCTAGAGC-CAGGATCTTCATTCCTGCTAAGCCAGAC 501 4. l_b CTCTAAGACATGTTGGGAAAGTCCCAAGAGC-CAGGATCTTCATTCCTGGTAAGGCAGAC 504 8.1 GTCTAAGACATTTTGGGAAAATCACTAGAGC-CAGGACCTTCATTCCTGGTAAGCCAGAG 498 8.7 GTCTAAGACATTTTGGGAAAATCCCTAGAGC-CAGGATCTTCATTCCTGGTAAGCCAGAG 500

8.6 GTCTAAGACATTTTGGGAAAATCCCTAGAGC- CAGGATCTTCATTCCTGGTAAGCCAGAG 503

8.8 GTCTAAGACATTTTGGGAAAATCCCTAGAGC-CAGGATCTTCATTCCTGGTAAGCCAGAG 503

8.5 TTCCCAGGGATTGTTGTTGAGTCCACGGCTCACGTCGTCCACACTC-TGAGGTCCCATGG 505 8.2 GATGCCATGAAAAAGGCATGCCTTCCCGGGCACAAGCAGGTAGATC- -ATCACTCCAAGG 507 4.1 a AAAACAGTAAAAATTTCATAG--AATGGGGCTAAGAATCTGCACTGCAAACTAACTCTTT 486 8.9 AGCCTGGAGACACACCCAAATTATGTCCCTCTTAGTTCAGGGAACATGTCCATTTTCGTC 583

8.10 AGCCTGAAGACACACCCAAATTATGTCCCTCTTAGTTCAGGGAACATGTCCATTTTCGTC 581 8.3 AGCCTGAAGACACACCCAAATTCTGTCCCTCTTACTTCAGGGAACATGTCCACTTTCGTC 536

8.11 AGCCTGAAGACACACCCAAATTCTGTCCCTCTTACTTCAGGGAACATGTCCACTTTCGTC 536 4.2_a AGCCGGAAGACACACCCAAATTCTGTCCCTCTTACTTCAGGGAACATGTCCACTTTCGGC 536

4.5 AGCCGGAAGACACACCCAAATTCTGTCCCTCTTACTTCAGGGAACATGTCCACTTTCGGC 557

4.3 AGCCGGAAGACACACCCAAATTCTGTCCCTCTTACTTCAGGGAACATGTCCACTTTCGGC 559 4.2_b AGCCGGAAGACACACCCAAATTCTGTCCCTCTTACTTCAGGGAACATGTCCACTTTCGGC 561

4.4 AGCCGGAAGACACACCCAAATTCTGTCCCTCTTACTTCAGGGAACATGTCCACTTTCGGC 561 4.1_b AGAATGAAGACACACCAAAATTCTGTCCCTCTTAATTCAGGGAACGTGTCCACTTTCGTC 564

8.1 AGCCGAAAGACACACCCAAATTCTGTCCCTCTTAGTTCAGGGAACAGGTCTACTTTCGTC 558

8.7 AGCCTGAAGACACACCCAAATGCTGTCCCTCTTAGTTCAGGGAACATGTCCACTTTCGTC 560

8.6 AGCCTGAAGACACACCCAAATGCTGTCCCTCTTAGTTCAGGGAACATGTCCACTTTCGTC 563

8.8 AGCCTGAAGACACACCCAAATGCTGTCCCTCTTAGTTCAGGGAACATGTCCACTTTCGTC 563 8.5 ATTCGCCACCCACATTCATCTACTCTCCTCTCTCTCTTCCTTACCTCCTTTGATCCCCTC 565

8.2 ACACCACCCTCATCCACCAAATATTTGGAGGGTACTGGAGATCTCAAATCAAGTGTCTCC 567 4. l_a CAGTTGATTTTATGCACAGAAATTATTGAGAATCCCCTTATCTAGATCCAACAGATCTGG 546

* * * * * 8.9 AGCATTAAAATTTTGGCACCAAATGTGCTAACTGCAATTCCACCATACAATGCATAACTG 643

8.10 AGCACTAAAATTTTTGCACCAAATGTGCTAACTGCAATTCCACCATGCAATGCGTAACTG 641

8.3 AGCATTACAATTTTTGCACCAAATGTGCTAACTGCAATTCCACCATACAATGCATAAATG 596

8.11 AGCATTACAATTTTTGCACCAAATGTGCTAACTGCAATTCCACCATACAATGCATAAATG 596 4.2_a AGCATTACAATTTTGGCACCAAATGTGCTAACTGCAATTCCACCATACAATGCGTAACTG 596 4.5 AGCATTACAATCTTGGCACCAAATGTGCTAACTGCAATTCCACCATACAATGCGTAACTG 617

4.3 AGCATTACAATTTTGGCACCAAATGTGCTAACTGCAATTCCACCATACAATGCGTAACTG 619 4.2_b AGCATTACAATTTTGGCACCAAATGTGCTAACTGCAATTCCACCATACAATGCGTAACTG 621

4.4 AGCATTACAATTTTGGCACCAAATGTGCTAACTGCAATTCCACCATACAATGCGTAACTG 621 4.1_b AGAATTAAAATTTTTGCACCAAATGTGCTAACTGGAATTCCACCATACAATGCATAACTG 624 8.1 AGCATTACAATTTTTGCACCAAATGTGCTAACTGCAATTCCACCATACAATGCATAACTG 618

8.7 AGCATTACAATTTTTGCACCAAATGTACTAACTGCAATTCCACCATACAATGCATAACTG 620 8.6 AGCATTACAATTTTTGCACCAAATGTACTAACTGCAATTCCACCATACAATGCATAACTG 623

8.8 AGCATTACAATTTTTGCACCAAATGTACTAACTGCAATTCCACCATACAATGCATAACTG 623

8.5 CCCA-TATGCTACCCCCCGCTACCAAACCTCTGCCAAGCATACCACCCTATCGGCAGCTA 624 8.2 ACTGCCACGGCATTTCAGACACTTTTGGCCCTTACCTGGACATCGCCCTGGATATCCAGG 627

4.l_a GCTTACATAGGTGCTATCAAGACTTAAGGAAGAAAATTTTCCTGACTCTATCCATACCTC 606

* *

8.9 GAAATAGAGGCAACATCTCATATCCTGAACAATTCATGTG AGAATCTAGGAGAC 697 8.10 TAAATGGAGGCAACATCTCAGATCCTGAACAATCGATGCG AGAATCCAGGAGAC 695

8.3 GAAATGGAGGGAACATCTCAGATCCTGAACAATCGATGCG AGAATCCAGGAGAT 650

8.11 GAAATGGAGGGAACATCTCAGATCCTGAACAATCGATGCG AGAATCCAGGAGAT 650

4.2_a GAAATGGAGGCAACATCTCCGATCCTGAACGATCGATGCG AGAATCCAGGATAT 650

4.5 GAAATGGAGGCAACATCTCCGATCCTGAACGATCGATGCG AGAATCCAGGATAT 671 4.3 GAAATGGAGGCAACATCTCCGATCCTGAACGATCGATGCG AGAATCCAGGATAT 673

4.2_b GAAATGGAGGCAACATCGCCGATCCTGAACGATCGATGCG AGAATCCAGGATAT 675

4.4 GAAATGGAGGCAACATCTCCGATCCTGAACGATCGATGCG AGAATCCAGGATAT 675

4. l_b GAAATGGAGGGAAAATCCCAGATCATGAACAATCAAAGCG AGAATCCAGGAGAC 678

8.1 GAAATGGAGGGAACATCTCAGATCATGAACAATCGATGAG AGAATCCAGGAGAT 672 8.7 GAAATGGAGGGAACATCTCAGAGCATGAACAACTGATGCG AGAATCCAGGAGAT 674

8.6 GAAATGGAGGGAACATCTCAGACCATGAACAATCGATGAG AGAATCCAGGAGAC 677

8.8 GAAATGGAGGGAACATCTCAGACCATGAACAATCGATGAG AGAATCCAGGAGAC 677

8 . 5 CTCTTCACTCCCA-ACTACATCGGCCGCATClsrNNNNlSr NN NNNNrøN-røNNNNN 677

8.2 AAGCTCAGAGTGTCAAGCAAGCTTTGGAACAGTTGGTGAAGCCCGAAGAACTCAATGGAG 687 4.1 a CAATTAGTAATAGATCTAGAGATTTAAAACTGAAATCCAGACCTC-CTGCTTCCATGTGC 665 8.9 ACACCGCTTATTTTTGCCTTTTCCCACTGAAACAATGGCTAGTATTAACAATGTTATGCT 757

8.10 ACACGGCTTATTTTTGCCTTTTCCCACTGAAACAAGGGCCAGTATTAACAATCTTATGCT 755 8.3 ACACGGCTGATTTTTGCGTTTTCCCTGTGAAACAAGGGCCAGTATTAAAAATGGTATGCT 710

8.11 ACACGGCTGATTTTTGCGTTTTCCCTGTGAAACAAGGGCCAGTATTAAAAATGGTATGCT 710 4.2_a GCACGGCTTATTTTGGCCTTTTCCCACTGAAACAAGGGCCAGTATTAAAAATGGCACGCT 710

4.5 GCACGGCTTATTTTGGCCTTTTCCCACTGAAACAAGGGCCAGTATTAAAAATGGCACGCT 731

4.3 GCACGGCTTATTTTGGCCTTTTCCCACTGAAACAAGGGCCAGTATTAAAAATGGCACGCT 733 4.2_b GCACGGCTTATTTTGGCCTTTTCCCACTGAAACAAGGGCCAGTATTAAAAATGGTACGCT 735

4.4 GCACGGCTTATTTTGGCCTTTTCCCACTGAAACAAGGGCCAGTATTAAAAATGGCACGCT 735 4.1_b ACACGGCTTATTTTGGCCTTTTCCCACTGAAACAAGGACCAGTATTAAAAATGGTATGCT 738

8.1 ACACGGCTTATTTTTGCCTTTTCCCTGTGAAACAAGGGCAAGTATTAAAAACTTTATGCT 732

8.7 ACACGGTTTATTTTTGCCATTTCCCAGTGAAACAAAAGCCAGTATTAAAAAGGTTATGCT 734

8.6 ACACGGCTTATTTTTGCCTTTTCCCTGTGAAACAAGGGCCAGCATTAAAAAGGTTATGCT 737

8.8 ACACGGCTTATTTTTGCCTTTTCCCTGTGAAACAAGGGCCAGCATTAAAAAGGTTATGCT 737

8.2 AGAATGCCTATCATTGTGGTCTTTGTCTCCAGAGGGCGCCGGCCTCCAAGACGTAAACTT 747 4. l_a AGTGTCCTTTCACTGTCCTGTTTTGCTTCACTTGATGAAGAGGATTTGAGAATAAATGAC 725

8.9 ATCCTTGGTTTCACTCCCCACTTTTAAATCTCTCGGATGTTTACTTCT-TGAGACAGG-- 814

8.10 ATCCTGGGTTTCACTCTCTGCTTTTAAATCTCTCCAATGTTTTCTTCT-TGAGACAGG-- 812

8.3 ATCCTCTGTTTCACTCCCTGCTTTTAAGTCTCC- -GATGTTT-CTTCT-TAAGACAGG- - 764

8.11 ATCCTCTGTTTCACTCCCTGCTTTTAAGTCTCC- -GATGTTT-CTTCT-TAAGACAGG- - 764 4.2_a ATCCTCTGTTTCACTCCCTGCTTTTAAACGTCTCCGATGT-TTCTCCC-TGAGACAGG-- 766 4.5 ATCCTCTGTTTCACTCCCTGCTTTTAAACGTCTCCGATGT-TTCTCCC-TGAGACAGG-- 787

4.3 ATCCTCTGTTTCACTCCCTGCTTTTAAACGTCTCCGATGT-TTCTCCC-TGAGACAGG-- 789 4.2_b ATCCTCTGTTTCACTCCCTGCTTTTAAACGTCTCCGATGT-TTCTCCC-TGAGACAGG- - 791

4.4 ATCCTCTGTTTCACTCCCTGCTTTTAAACGTCTCTGATGT-TTCTCCC-TGAGACAGG-- 791 4. l__b ATACTCTGTTTCACTCCCTGCTTTTAAACGTCTCCGATGT-TTCTTCT-TGAGACAGG-- 794 8.1 GTCTTCTATTTCACTGCCTGCTTTTAAACGTCTCCGATGTATTCTTCT-TGAGAAAGG-- 789

8.7 ACCCTCTGTTTCACTCACTGCTTTTAAACGTCTCCGATGTTTTCTTCT-TCAGACAGG-- 791 8.6 ATCTTCTGTTTCACTCCCTGCTTTTAAACGTCTCCGATGTTTTCTTCT-TCAGACAGG-- 794

8.8 ATCTTCTGTTTCACTCCCTGCTTTTAAACGTCTCCGATGTTTTCTTCT-TCAGACAGG-- 794 8.2 TACACACTTCTGCCAAGATCCTCATCCTCGTATTGAAGAGATTCTCCGATGTCACAGGCA 807

4. l_a CACATGATTCAACTCCTCCTCAGCTCTGAGCAAT-ATAGCCCTGTCCTGGCAAACAAGAA 784

* * * * * * *

8.9 GCGTC-ACTGCCGTCACCCACGCTTTTCTACGGT GTAATTTTTGTTGTTCGCTT 867 8.10 GCCTC-ACTCCCGTCACCAGGGCTTTTCTACGGT GCAATTTTCGGTGTTTGCTT 865

8.3 GCCTC-ACTTCCTTCCCCCTGACTTTTCTACGGT ATAATTTTCGTTGTTTGCTT 817

8.11 GCCTC-ACTTCCTTCCCCCTGACTTTTCTACGGT ATAATTTTCGTTGTTTGCTT 817

4.2_a GCCTC-ACTTCCGTCAGCCGGGCTTTTCCACGGT ATAATTTTCCTTGTTTGCTT 819 .5 GCCTC-ACTTCCGTCAGCCGGGCTTTTCCACGGT ATAATTTTCCTTGTTTGCTT 840 4.3 GCCTC-ACTTCCGTCAGCCGGGCTTTTCTACGGT ATAATTTTCCTTGTTTGCTT 842

4.2_b GCCTC-ACTTCCGTCAGCCGGGCTTTTCTACGGT ATAATTTTCCTTGTTTGCTT 844

4 . 4 GCCTC-ACTTCCGTCAGCCGGGCTTTTCTACGGT ATAATTTTCCTTGTTTGCTT 844

4. l_b GCCTC-ACTGCCGTCCGCCGGGCTAT-CTAGAGT ATAATTTTCAGTGTTTGCTT 846

8.1 GCCTC-ACTACTGTCACCTGGGCTTTTCTAAGGT ATAATTTTCCTTGTTTGCTT 842 8.7 GCCTC-ACTCCCGTCACCCGGGCTTTTCTACGGT ATAATTTTCCTTGTTTGCTT 844

8.6 GCCTC-ACTCCCGTCACCCGGGCTTTTCTACGGT ATAATTTTCCTTGTTTGCTT 847

8.8 GCCTC-ACTCCCGTCACCCGGGCTTTTCTACGGT ATAATTTTCCTTGTTTGCTT 847

8.5 GCCTC-ACTCCCGTCACCCGGGCTTTTCTACGGT ATAATTTTCCTTGTTTGCTT 847

8.2 ACAAA-ATTGCCAAGAATGTGCAATATCCTGAGTGCCTTGACATGCAGCCATACATGTCT 866 4.1 a GCTCCTGCAGTAGTAGAGGAGGCAAATATACGTT CACTAATCTAACATACAAG 837 8.9 TTGTCAAATTTAGAAATTTTCATTTCA- -TCTCTATCAAATGTTGCTCCATT ATCA 921

8.10 TTGTCAAATTTAGAACTTTTCATTTCA- -TCTCTATCAAATGTTGATCCATT ATCA 919

8.3 TTGTCAAAATTAGAACTTTTTATTTCA- -TCTCTATGAAATGTTGATCCATT ATCA 871

8.11 TTGTCAAAATTAGAACTTTTTATTTCA- -TCTCTATGAAATGTTGATCCATT ATCA 871 4.2_a TTGTCCAAATTAGAACTTTTTATTTCA- -CCTCTAGGAAACGTTGATCCATT ATCA 873

4.5 TTGTCCAAATTAGAACTTTTTATTTCA- - CCTCTAGGAAACGTTGATCCATT ATCA 894

4.3 TTGTCCAAATTAGAACTTTTTATTTCA- -TCTCTAGGAAACGTTGATCCATT ATCA 896

4.2_b TTGTCCAAATTAGAACTTTTTATTTCA- -TCTCTAGGAAACGTTGATCCATT ATCA 898

4.4 TTGTCCAAATTAGAACTTTTTATTTTA- -TCTCTAGGAAACGTTGATCCATT ATCA 898 4.1_b TTGTCAACCTTAGAACATTTTATTTCG- -TCTCTATGAAATGTTGATCCATT ATCA 900

8.1 TTGTCAAAATTAGAACATTTTATTTCA- -TATCTATGAAATGTTGATCCATT ATCA 896

8.7 TTGTCAAAATTAGAACTTTTTATTTCA- -TCTCTATGAAATGTTGATCCATT ATCA 898

8.6 TTGTCAAAATTAGAACTTTTTATTTCA- -TCTCTATGAAATGTTGAGCCATT ATCA 901

8.8 TTGTCAAAATTAGAACTTTTTATTTCA- -TCTCTATGAAATGTTGAGCCATT ATCA 901 8.5 TTGTCAAAATTAGAACTTTTTATTTCA- -TCTCTATGAAATGTTGATCCATT ATCA 901

8.2 CAGCAGAACACAGGACCTCTTGTCTATGTCCTCTATGCTGTGCTGGTCCACGCCGGGTGG 926 4. l_a - -GCAGTAGGCACTGTACCATAAACAAG-ACACTGTGGGGGTTCAGACCAGG GGCAA 891

* * ** ** * 8.9 CATACGTATGA-AAATATTATCACGCGTGCTGTGAGATACGTTGTTTTTATTTTCATCAA 980

8.10 CATACGTATGA-AAATATTATCACCCATGCTGTGAGATACGTTGTTTTTATTTTCATCAA 978

8.3 CATACGTATGG-AAAGACTATCACCCATGCTGTGAGATACGTTGTTTTTATTTTCATCAA 930

8.11 CATACGTATGG-AAAGACTATCACCCATGATGTGAGATACGTTGTTTTTATTTTCATCAA 930 4.2_a CATACGTATGG-AAATATTATCACACATGCTGTGAGATACGTTGTTTTTATTTTCATCAA 932 4.5 CATACGTATGG-AAATATTATCACACATGCTGTGAGATACGTTGTTTTTATTTTCATCAA 953

4.3 CATACGTATGG-AAATATTATCACACATGCTGTGAGATACGTTGTTTTTATTTTCATCAA 955 4.2_b CATACGTATGG-AAATATTATCACACATGCTGTGAGATACGTTGTTTTTATTTTCATCAA 957

4.4 CATACGTATGG-AAATATTATCACACATGCTGTGAGATACGTTGTTTTTATTTTCATCAA 957 4. l_b CATACACATGG-AAATATTATCACCCACGGTGTCAGATACGTTGTTTTTATTTTCATCAC 959 8.1 CATACGTATGG-AAATAGTATCACCAATGCTGTGAGATAAGTTGTTTTTATTTTGGTCAA 955

8.7 CGTAAGTATGG-AAATAGTATCAGCCACGCTGTGAGATACGTTGTTTTTATTTTCATCAG 957 8.6 CATACGTATGG-AAACAGTATCACCCATGCTGTGAGATACGTTGTTTTTATTTTCATCAG 960 8.8 CATACGTATGG-AAACAGTATCACCCATGCTGTGAGATACGTTGTTTTTATTTTCATCAG 960

8.5 CGTAAGTATGG-AAATAGTATCAGCCACGCTGTGAGATACGTTGTTTTTATTTTCATCAG 960 8.2 AGTTGTCACAACGGACATTACTTCTCTTATGTCAAAGTTCAAGAAGGCCAGTGGTATAAA 986

4. l_a AGTGGGGATTG- - -ATAGGGCTAGTAAAGTCTAGGAAGTGTTCACTAACAAAATGTCTAA 948

* * * * * *

8.9 TTCTTTTGTAAAACAAAGGTTATAGTTGGGATACCTTCTGATTTCTCAAGTTTTTTGTTT 1040 8.10 TTCTTTAATAAACCAAAGGTTATAGTTGGGATACCTTCTGATTTCTCAAGTTTTTTGTTT 1038

8.3 TTCTTTAATAAACCAAAGGTTATAGTTGGGATACCTTCCGATTTCTCTAGTTTTTTGTTT 990 8.11 TTCTTTAATAAACCAAAGGTTATAGTTGGGATACCTTCCGATTTCTCTAGTTTTTTGTTT 990 4.2_a TTCTTTAATAAACAAACGGTTATAGCTGGGATACCTTCTGAGTTCTCAAGTTTTTTGTTT 992

4.5 TTCTTTAATAAACAAACGGTTATAGCTGGGATACCTTCTGAGTTCTCAAGTTTTTTGTTT 1013 4.3 TTCTTTAATAAACAAAAGGGTATAGCTGGGATACCTTCTGAGTTCTCAAGTTTTTTGTTT 1015

4.2_b TTCCTTAATAAACAAAAGGTTATAGCTGGGATACCTTCTGAGTTCTCAAGTTTTTTGTTT 1017

4.4 TTC-TTAATAAACAAAAGGTTATAGCTGGGATACCTTCTGAGTTCTCAAGTTTTTTGTTT 1016 4. l_b TTC AAGAAAAAAAAGGGTATAGTTGGGATACCTTCTGATTTCTCAAGATTTTTCTTT 1016

8.1 TTCTTTAATAAACAAAAGCTTATAGTTGGGATACCTTCTGATTTCTCAAGGTTTTTGTTT 1015 8.7 TTATTTAATAAACAAAAGCTTATAGTTGGGATACCTTTGGATTTCTCAAGTTTTTTGTTT 1017

8.6 TTCTTTAATAAACAAAAGCTTATAGTTGGGATACCTTTGGATTTCTCAAGTTTTTTGTTT 1020

8.8 TTCTTTAATAAACAAAAGCTTATAGTTTGGATACCTTTGGATTTCTCAAGTTTTTTGTTT 1020

8.5 TTATTTAATAAACAAAAGCTTATAGTTGGGATACCTTTGGATTTCTCAAGTTTTTTGTTT 1020

8.2 ATGGATGATGCCGAGGTCACTGCCTCTGGCATCACCTCTG TCCTGAGTCAACAGGCC 1043 4.1 a TTATTAACTAAACTAAATGGTTTC-TCAACATGACCTAATTAATTGTAACTTACTATAAA 1007 8.9 CATGTTTTCTT 1051

8.ιo CAGGTTTTCTT 1049

8.3 CATGTTTTCTTTCTTTTTTTTTTTTTTTTTTTT GAGACGGGGTCTCGCTCT 10 1

8.11 CATGTTTTCTTTCTTTTTTTTTTTTTTTTTTTTTTTTTTTTTGAGACGGGGTCTCGCTCT 1050 4.2_a CGTGTTTTCTT 1003

4.5 CGTGTTTTCTT 1024

₄.3 CGTGTTTTCTT 1026

4.2_b CGTGTTTTCTT 1028

4.₄ CGTGTTTTCTT 1027 4.1_b CATATTTTCTT -- 1027

8. i CATGTTTTCTT 1026

8.7 CAAGTTTTCTT 1028

8.6 CATGTTTTCTT 1031

8.8 CATGTTTTCTT 1031 8.5 CAAGTTTTCTT 1031

8.2 TATGTCCTCTTTTACATCC 1062

4. l_a TGGTTGTTTGTTCA 1021

* * * 8.9

8.10

8.3 GTCGCCCAGGCCGGACTGCGGACTGCAGTGGCGCAATCTCGGCTCACTGCAAGCTCCGCT 1101

8.11 GTCGCCCAGGCCGGACTGCGGACTGCAGTGGCGCAATCTCGGCTCACTGCAAGCTCCGCT 1110 4.2_a 4.5

4.3

4.2_b

4.4

₄ _b 8.1

8.7

8.6

8.8

8.5 8.2

4. l a

8.9 8.10

8.3 TCCCGGGTTCACGCCATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGGACTACAGGCGCCC 1161

8.11 TCCCGGGTTCACGCCATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGGACTACAGGCGCCC 1170

4.2_a 4.5 4.3

4.2_b 4.4 4.l_b 8.1 8.7 8.6 8.8 8.5 8.2 4.1 a 8.9 A 1052

8 .10 A 1050

8 .3 GCCACCGCGCCCGGCTAATTTTTTGTATTTTTAGTAGAGACGGGGTTTCACTTTGTTAGC 1221

8 .11 GC-ACCGCGCCCGGCTAATTTTTTGTATTTTTAGTAGAGACGGGGTTTCACCTTGTTAGC 1229

4 .2 a

4 .5

4 .3

4 .2 b

4 .4

4 .1 b

8 .1

8 .7

8 .6

8 .8

8 .5

8 .2

4 . l_a

8 .9

8 .10

8 .3 CAGGATGGTCTCGATCTCCTGACCTCATGATCCACCCGCCTCGGCCTCCCAAAGTGCTGG 1281

8 .11 CAGGATGGTCTCGATCTCCTGACCTCATGATCCACCCGCCTCGGCCTCCCAAAGTGCTGG 1289

4 .2 a

4 .5

4 .3

4 .2 b

4. .4

4. .1 b

8. .1

8, .7

8, .6

8. .8

8. .5

8. .2

4. ,l_a

8. .9 AACTGCCGTCGCAC 1066

88.. .1100 AACTGCCGTCGCAC 1064

8. .3 GATTACAGGCGTGAGCCACCGCGCCCGGCCGTTTCATGTTTTCTTAAACTGCCATCGCAC 1341

8. ,11 GATTACAGGCGTGAGCCACCGCGCCCGGCCGTTTCATGTTTTCTTAAACTGCCATCGCAC 1349

4. .2 a AAACTGCCGTCGCAC 1018

4. ,5 AAACTGCCGTCGCAC 1039

44.. .33 AAACTGCCGTCGCAC 1041

4. .2 b AAACTGCCGTCGCAC 1043

4. .4 AAACTGCCGTCGCAC 1042

4. .1 b AAACTGCCGTCGGAC 1042

8. .1 AAACTGCCGCCGCAC 1041

88.. ,77 AAACTGCCGCCGCAC 1043

8. .6 AAACTGCCGCCGCAC 1046

8. .8 AAACTGCCGCCGCAC 1046

8. .5 AAACTGCCGCCGCAC 1046

8. .2 ACAAGAGTGAATGGGAAAGACAC 1085

44.. 11_ aa TAAACCTTAATCTTTT 1037

** 8 . 9 GTCCAAAACCACTCGCTATGCAATGTCTTG-ACCATCTCTCTTTTCTGGCAAATATAAAT 1125

8 . 10 GTCCGAAACCATTCACTATACAATGTCATT-TTCATCTCTCTTTTCTGGCACACATAAAT 1123

8 . 3 ATCCGAAATCATTCACTATACAATGTCATG-ACCATCTCTCTTTCCTGGCAAACATAAAT 1400

8 . 11 ATCCGAAATCATTCACTATACAATGTCATG-ACCATCTCTCTTTTCTGGCAAACATAAAT 1408

4 . 2_a GTCCGAAACCGCTCACTATGCAGTGTCATG-ACCGTCTCTCTTTTCTGGCAAACATAAAT 1077

4 . 5 GTCCGAAACCGCTCACTATGCAGTGTCATG-ACCGTCTCTCTTTTCTGGCAAACATAAAT 1098

4 . 3 GTCCGAAACCGCTCACTATGCAGTGTCATG-ACCGTCTCTCTTTTCTGGCAAACATAAAT 1100

4 . 2_b GTCCGAAACCGCTCACTATGCAGTGTCATG-ACCGTCTCTCTTTTCTGGCAAACATAAAT 1102

4 . 4 GTCCGAAACCGCTCACTATGCAGTGTCATG-ACCGTCTCTCTTTTCTGGCAAACATAAAT 1101 4 4. . ll_bb GTCAGAAACTACTCACTATACAATGTCGTG-ACAATCTACATTTTCGGGCAAACACAAAT 1101

8 . 1 GTCCGAAACCACTCACTATACAATGTCAGG-ACCATCTCTCTTTTCTGGCACACATAAAT 1100

8 . 7 GTCCGAAACCACTCACTATACAATGTCAGG-ACCATCTCTCTTTTCTGGCACACATAAAT 1102

8 . 6 GTCCGAAACCACTCACTATACAATGTCAGG-ACCATCTCTCTTTTCTGGTACACATAAAT 1105

8 . 8 GTCCGAAACCACTCACTATACAATGTCAGG-ACCATCTCTCTTTTCTGGTACACATAAAT 1105 8 8. .55 GTCCGAAACCACTCACTATACAATGTCAGG-ACCATCTCTCTTTTCTGGCACACATAAAT 1105

8 . 2 AGTGAGAGTGTGTCAAGAGGCAGGGA-ACC-AAGAGCCCTCGGCGCTGA-AGACACAGAC 1142

4 . l_a GCCAAAATATTTGTAGCTTATGTTCCCATTTAACAAGGTTTTCTGGTCAAAACTGTGCAC 1097

* * * 8 8. .99 TTTCGGAATGTCATCAATTAGTCTCTCGGTGATTGCATTATTTCCCCAAAGTCTTTTACA 1185

8 . 10 TTGCGGAATGTCATCAATTAGTCTCTCGGTGATTGCATGATTTCCCCAAAGTCTTACACA 1183

8 . 3 TTGGGGATTGTCATCAATTAGTCTCTCAGTGACTGCATGATTTCCACAAAGTCTTTCACA 1460

8 . 11 TTGGGGATTGTCATCAATTAGTCTCTCGGTGACTGAATGATTTCCACAAAGTCTTTCACA 1468

4 . 2_a TTGGGGATTGTCATCAATTAGTCTCTCGGGGATTGCATGATTTCCCCAAAGGCTTTCACA 1137 4 4. .55 TTGGGGATTGTCATCAATTAGTCTCTCGGGGATTGCATGATTTCCCCAAAGGCTTTCACA 1158

4 . 3 TTGGGGATTGTCATCAATTAGTCTCTCGGGGATTGCATGATTTCCCCAAAGGCTTTCACA 1160

4 . 2_b TTGGGGATTGTCATCAATCAGTCTCTCGGGGATTGCATGATTTCCCCAAAGGCTTTCACA 1162

4 . 4 TTGGGGATTGTCATCAATTAGTCTCTCGGGGATTGCATGATTTCCCCAAAGGCTTTCACT 1161

4 . l_b TTGGGGAATGTCATCAAATAGTCTCCCGCTGATTGCATGATT-CCACAAAGTCCTACACA 1160 8 8. .11 TTGGGGAATGTCATCAATTAGTCTCTCGGTGATTGCATGATTTCCCCAAAGTCTTTCACA 1160

8 . . 7 TTGGGGAATGTCATCAATTAGTCTCTCGGTGATTGCATGATTTCCCCAAAGTCTTTCACA 1162

8 , . 6 TTGGGGAAAGTCATCAATTAGTCTCTCGGTGATTGCATGATTTCCCCAAAGTCTTTCACA 1165

8 , . 8 TTGGGGAAAGTCATCAATTAGTCTCTCGGTGATTGCATGATTTCCCCAAAGTCTTTCACA 1165

8 . . 5 TTGGGGAATGTCATCAATTAGTCTCTCGGTGATTGCATGATTTCCCCAAAGTCTTTCACA 1165 8 8.. .22 A-GGCGAGCAACG-CAAGGAGAGCTCAAGAGAGACTACCCCTGCCTCCAGG- -TACCCGA 1198

4 . , l_a CCACATCATTCTAATGAACTTAGTGTCCAATAAAACATGGACTCTCAGTCGTCCCACGGA 1157 * * * * *

8 . . 9 GTCTAGTTTGTGCACTGAGTATCTCTTCAAACTTCAGTGCATGTTTCTACGACTTAATGC 1245 8 8., .1100 CTCTACATTGTGCACTGAGTATCTCTTCAGACTTTAGTGCATGTTTCTACCACTTGATGC 1243

8 . , 3 GTCTACTTTGTGCACTGAGTATCTCTTCAAACTTCAGTGT- -GTTTCTACCATATGATGC 1518

8 . . 11 GTCTACTTTATGCACTGAGTATCTCTTCAAACTTCAGTGTATGTTTCTACCATTTGATGC 1528

4 . 2_a GTCTACTTTGTGCACTGAGTATCTCTTCAAACTTCAGTGCATGTTTCTACCATTTGATTC 1197

4 . . 5 GTCTACTTTGTGCACTGAGTATCTCTTCAAACTTCAGTGCATGTTTCTACCATTTCATGC 1218 4 4.. .33 GTCTACTTTGTGCACTGAGTATCTCTTCAAACTTCAGTGCATGTTTCTACCATTTGATTC 1220

4 . , 2_b GTCTACTTTGTGCACTGAGTATCTCTTCAAACTTCAGTGCATGTTTCTACCATTTGATGC 1222

4 . , 4 GTCTACTTTGTGCACTGAGTATCTCTTCAAACTTCAGTGCATGTTTCTACCATTTGATGC 1221

4 . , l_b GTCTACATTGTGCACTGAGTATCTCTTCAAACTTCAGTGCTTCTTTCTACCATATGATGC 1220

8 . , 1 GTCTACTTTGTGCAATGAGTATCTCTTCAAACTTCAGTGCATATTTCTACCATTTGATGC 1220 8 8.. .77 GCCTACTTTGTGCACTGAGTATCTCTTCAAACTTTAGTGCATGTTTCTACCATTTGATGC 1222

8 . , 6 GTCTACTTTGTGCACTGAGTAACTCTCCAAACTTCAGTGCATGTTTCTACCATTTGATGC 1225

8 . . 8 GTCTACTTTGTGCACTGAGTAACTCTCCAAACTTCAGTGCATGTTTCTACCATTTGATGC 1225

8 . . 5 GCCTACTTTGTGCACTGAGTATCTCTTCAAACTTTAGTGCATGTTTCTACCATTTGATGC 1225

8 . , 2 GTTGGACGAGCACTTGGTGGAAAGAGCCACTCAGGAAAGCAC-CTTAGACCACTGGAAAT 1257 4 4..1 1 aa AGTTATTTTGTGTGCATAGTACATCTCTGTGAATATGCCTAATGAGGTATGGAAGGACAC 1217 8.9 TTTATTATTCAGCAATCTAGCTTCCACAAGAGCATTTAATGTAAAGACTTGTCT-TTTTC 1304

8.10 TTTATTACTT-GCCATCTAGCTTCCACAAGAGCATTTCATGCAAAGACTTCTCT-TGTTC 1301 8.3 TTTATTATTTGGCAACCTAGCTTCCAAAAGAGCATTTCATGCAAAGACTTGTCT-TGTTA 1577

8.11 TTTATTATTTGGCAACCTAGCTTCCAAAAGAGCATTTCATGCAAAGACTTGTCT-TGTTA 1587 4.2_a TTTCTTATTTGGCAATCTAGCTTCCACAAGAGCATTTCACGCAAAGACTTGTCT-TGTTC 1256

4.5 TTTCTTATTTGGCAATCTAGCTTCCACAAGAGCATTTCATGCAAAGACTTGTCT-TGTTC 1277

4.3 TTTCTTATTTGGCAATCTAGCTTCCACAAGAGCATTTCATGCAAAGACTTGTCT-TGTTC 1279 4.2_b TTTATTATTTGGCAATCTAGCTTCCACAAGAGCATTTCATGCAAAGACTTGTCT-TGTTC 1281

4.4 TTTATTATTTGGCAATCTAGCTTCCACAAGAGCATTTCATGCAAAGACTTGTCT-TCTTC 1280 4.1_b TTTATCATTTGGCAATCTAGCTTCCACAAGAGCATTTCATGCAAACACTTGTCT-TGTTG 1279

8.1 TTTATTATTTGGCAACCTAGCTTCCACAAGAGCATGTCAGGCAAAGAGTTCTCT-TGTTC 1279 8.7 TTTATTATTTGGCAGCCTAGCTTCCACAAGAGCATTTCATGCAAAGACTTGTCT-TGTTC 1281

8.6 TTTATT TGGCAGCCTAGCTTCCACAAGAGTATTTCATGCAAAGACTTGTCT-TGTTC 1281

8.8 TTTATT TGGCAGCCTAGCTTCCACAAGAGTATTTCATGCAAAGACTTGTCT-TGTTC 1281 8.5 TTTATTATTTGGCAGCCTAGCTTCCACAAGAGCATTTCATGCAAAGACTTGTCT-TGTTC 1284

8.2 TCCTCCAAGAGCAAAACAAAACGAAGCCTGAGTTCAACGTCAGAAAACTTGAAGGTACCC 1317 4. l_a TT-ATTATCCAAACAGAGACATTCCACTGGTGCTAGAGAGCCACAGAC--GGAAGTTTTC 1274

* * * * * * * 8.9 TCCACTGGCAGGTAATTTCACTCGGATATAGAATCATTAGGCTGAACATGGAAAGGTTAT 1364

8.10 TCCACTGGCAGGTAATTTCACTCGGATAGAGAATCAATAGGCTGAACGTGGAAAGGTTAT 1361

8.3 TCCACTGGCAGCTAATTTCATTCGGATAGAGAATCAATAGGCTGAACGTGGAAAGCTTAT 1637

8.11 TCCACTGGCAGCTAATTTCATTCGGATAGAGAATCAATAGGCTGAACGTGGAAAGCTTAT 1647 4.2_a TCCACTGGCAGGTAATTTCACTCGGACAGAGAATCAATAGGCTCAACGTGGAAAGCTTAT 1316 4.5 TCCACTGGCAGGTAATTTCACTCAGATAGAGAATCAATAGGCTCAACGTGGAAAGCTTAT 1337

4.3 TCCCCTGGCAGGTAATTTCACTCGGACAGAGAATCAATAGGCTCAACGTGGAAAGGTTAT 1339 4.2_b TCCACTGGCAGGTAATTTCACTCGGACAGAGAATCAATAGGCTCAACGTGGAAAGGTTAT 1341

4.4 TCCACTGGCAGGTAATTTCACTCGGACAGAGAATCAATAGGCTCAACGTGGAAAGGTTAT 1340 4.1_b TCCACTGGCAAGTAATTCAACACGGATAGAGAATCAATAGGCTCAACGTGGAAAGGTTAT 1339 8.1 TCCACTGGAAGGTAATTTCATTCGCACAGAGAATCAATAGGCTGAACGTAGAAAGGTTAT 1339

8.7 TCCACTGGCCAGTAATTTCACTCGGATAGAGAGTCAATAGGCTGAACGTGGAAAGGTTAT 1341 8.6 TCCACTGGCAGGTAATTTCACTCGGATAGAGAATCAATAGTCTGAACGTGGAAAGGTTAT 1341

8.8 TCCACTGGCAGGTAATTTCACTCGGATAGAGAATCAATAGTCTGAACGTGGAAAGGTTAT 1341

8.5 TCCACTGGCCAGTAATTTCACTCGGATAGAGAGTCAATAGGCTGAACGTGGAAAGGTTAT 1344 8.2 TGCCTCCCAACGTACTTGTGATTCATCAATCAAAATACAAGTGTGGGATGAAAAA-CCAT 1376

4. l_a TCTGCCTACTGGAAATAAAGC CAAGCTTTCTTCTTTCCTCAGCCGTGAGGATTGC 1329

* * * * *

8.9 CGCTGGGAGGTCTGTTTGATTCCACGGATCTCTCCTTTTTTATTGAGGAAAAAAATATGC 1424 8.10 CGCTGGAAGGTCTGTTTGATTCCACGGATCTCTCCTTTCTTATTAAGGAAAAAGATACAC 1421

8.3 CGCTGGAAGGTTTGTTTGTTTCCACGGATCTCTCCTTTCTTATTAGGGAAAAAAATACGC 1697 8.11 CGCTGGAAGGTTTGTTTGTTTCCACGGATCTCTCCTTTCTTATTAGGGAAAAAAATACGC 1707 4.2_a CGCTGGAAGGTCTGTTTGATTCCACGGATCTCTCCTTTCTCATTAGGGAAGAAAATACGC 1376

4.5 CGCTGGAAGGTCTGTTTGATTCCACGGATCTCTCCTTTCTCATTAGGGAAGAAAATACGC 1397 4.3 CGCTGGAAGGTCTGTTTGATTCCACGGATCTCTCCTTTCTCACTAGGGAAGAAAATACGC 1399

4.2_b CGCTGGAAGGTCTGTTTGATTCCACGGATCTCTCCTTTCTCACTAGGGAAGAAAATACGC 1401

4.4 CGCTGGAAGGTCTGTTTGATTCCACGGATCTCTCCTTTCTCACTAGGGAAGAAAATACGC 1400 4.l_b CGCTGGAAGGTCTGTTTGATTCCACGGATCTCTCCTTTCTCATTAGGGAAGAAAATACGC 1399

8.1 CGCTGGAAGCTCTGTTTCATTCCACGGATCTCTCCTTTCTTATTAAAGAAAAAAATACGC 1399 8.7 CCCTGGAAGGTCTGTTTGATTCCACGGATCTCTCCTTTATTATTAAGGAAGAAAATACGC 1401

8.6 CGCTGGAAGGTCTGTTTGATTCCACGGATCTCTCCTTTATTATTAAGGAAAAATATACGC 1401 8.8 CGCTGGAAGGTCTGTTTGATTCCACGGATCTCTCCTTTATTATTAAGGAAAAATATACGC 1401

8.5 CCCTGGAAGGTCTGTTTGATTCCACGGATCTCTCCTTTATTATTAAGGAAGAAAATACGC 1404

8.2 CATCCTGAA- - CAGCAAAGCTCCCTGCTAAACCTCTCTTCGACGAACCCGACAGATCAGG 1434 4.1 a TGACCTCC--TCTTTATCATTCTCTCTCTCTCTTTTTTTTTAATGAGCCAAGCTCCACCA 1387 8 . 9 TGTGCTAATTACTGTACTTCATTGCCTATTCTCAGGTCAGAAAG CGCACTTCAGA 1479

8 . 10 TGCGCTAATTACTATACTTCATTGACTATTCTCAGGTCAGAAAG CGCACTTCCGA 1476

8 . 3 TGTGCTAAATACTATACTTCATTGACTATTCTCAGGTCAGAAAG CGCACTTCCGA 1752

8 . 11 TGTGCTAAATACTATACTTCATTGACTATTCTCAGGTCAGAAAG CGCACTTCCGA 1762

4 . 2 a TGTGCTAAATACTATACTTCATTGACTATTCTCAGGTCAGAAAG CGCACTTTCGT 1431

4 . 5 TGTGCTAAATACTATACTTCATTGACTATTCTCAGGTCAGAAAG CGCACTTTCGA 1452

4 . 3 TGTGCTAAATACTATACTTCATTGACTATTCTCAGGTCAGAAAG CGCACTTTCGA 1454

4 . 2_b TGTGCTAAATACTATACTTCATTGACTATTCTCAGGTCAGAAAG CGCACTTTCGA 1456

4 . 4 TGTGCTAAATACTATACTTCATTGACTATTCTCAGGTCAGAAAG CGCACTTTCGA 1455 4 4. .1l__bb TGTGCTAAATATTATACTTCATTGACTATTCTCAGGTCAGAAAG CACACTTCCGA 1454

8 . 1 TGTGCTAAATACCATACTTCATTGACTAATCTCAGGTCAGAAAG CACACTTCCGA 1454

8 . 7 TGTGCTAAATACTATACTTCATTGACTATTCTCAGGTCAGAAAG CGCACTTCAGA 1456

8 . 6 TGTGCTAAATACTATACTTCATTGACTATTCTCAGGTCAGAAAG TGCACTTCAGA 1456

8 . 8 TGTGCTAAATACTATACTTCATTGACTATTCTCAGGTCAGAAAG TGCACTTCAGA 1456 8 8. .55 TGTGCTAAATACTATACTTCATTGACTATTCTCAGGTCAGAAAG CGCACTTCAGA 1459

8 . 2 AGT-CCATGAACACTGGCACACTCGCTTCTCT GCAAGGGAG GAC-CAGGAGA 1484

4 . l_a AATAATAAGATAAACTTTGTGCAAGACTTGGTAAGAGTAGAGTGTCTGACACCTTATGGT 1447 * * ** * * * 8 8. .99 CTTCT CCTTCTATCGCTGAAAGGAT-GATGGTATCTGCCAAAAGCACATAC-TCGGA 1534

8 . 10 CTTCTTGTCCTTCCATCGCTGAGAGGAT-GATGGTATCTGCCAAAAGCACATAT-TTGGA 1534

8 . 3 CTTCTTCTCTTTCCGTCGCTGAGAGGAT-GATGGTAGCTGCCAAAAGCACATAC-TTGGA 1810

8 . 11 CTTCTTCTCTTTCCGTCGCTGAGAGGAT-GATGGTAGCTGCCAAAAGCACATAC- TGGA 1820

4 . 2_a CTTCTTGTCCTTCCGTCGCGGAGAGGAT-GATGGCAGCTGCCAAAAGTACATAC- TGGA 1489 4 4. , .55 CTTCTTCTCTTTCCGTCGCTGAGAGGA -GATGGCAGTTGCCAAAAGTACATAC- TGGA 1510

4 . 3 CTTCTTGTCCTTCCGTCGCTGAGAGGAT-GATGGCAGCTGCCAAAAGTACCTAC-TTGGA 1512

4 . 2_b CTTCTTGTCCTTCCGTCGCTGAGAGGAT-GATGGCAGCTGCCAAAAGTACCTAC-TTGGA 1514

4 . 4 CTTCTTGTCCTTCCGTCGCTGAGAGGAT-GATGGCAGCTGCCAAAAGTAACTAC-TTGGA 1513

4 . . 1 b ATTCTTGTCCTTCGGTCACTGAGAGGAT-GATGGTAGCTGCCAAAAGTACATAC-TTGGA 1512 8 8., .11 TTTCTTGTCCTTCTGTCGCTGAGAGGAT-GATGATAGCTGCCAAAAGTACATAC-TTGGA 1512

8 . . 7 CTTCTTGTCCTTCCGTTGATGAGAGGAT-GACGGTAGCTGCCAAAAGTACATAC-TTGGA 1514

8 . . 6 CTTCTTGTGCTTCCATCGCTGAGAGGAT-GATGGTAGCTGCCAAAAGTACATAC-TTGGA 1514

8 . . 8 CTTCTTGTGCTTCCATCGCTGAGAGGAT-GATGGTAGCTGCCAAAAGTACATAC-TTGGA 1514

8 . . 5 CTTCTTGTCCTTCCGTTGATGAGAGGAT-GACGGTAGCTGCCAAAAGTACATAC-TTGGA 1517 8 8.. .22 GCCAAAGGGAAGA ACAAACACTGCAAGAGGGCTCTGC-TTGTG 1526

4 . , l_a GCTATAATACTCAAAGCAAAAGCAAAATCGCCTAGGACCAGAAAAGGGAGTCACATAGGA 1507

* * * * * * *

8 . , 9 AGT- - -ACATCCCAGCACAAACACACACACACACA CACGCACACA 1576 8 8..1 100 AGT---ACATCCCGGCACAAACACACACACACACA CACACACACA 1576

8 . . 3 GGT- - -TCATCCCAGCACAAACACACACACACAAA CACACAAACA 1852

8 . . 11 GGT TCATCCCAGCACAAACACACACACACAAA CACACAAACA 1862

4 . , 2_a AGT- - -TCATCCCAGCACAAACACACACACACACGC- -CCCCCCCACACACACACACACA 1544

4 . 5 AGT- - -TCATCCCAGCACAAACACACACACACACGCGCCCCCCCCACACACACACACACG 1567 4 4.. .33 GGT TCATCCCAGCACAAACACACACACACACACGCCCCCCCC CACACACACACA 1566

4 . 2_b GGT- - -TCATCCCAGCACAAACACACACACACACACGCCCCCCCC CACACACACA 1566

4 . . 4 GGT- - -TCATCCCAGCACAAACACACACACACACATGCCCCCCCC ACACACACACA 1566

4 . l b AGT- - -TCATCCCAGCACAAACACACATACACACACGCCCCCCCC CACACACACA 1564

8 . 1 AGT- - -TCATCCCAGCACGAGCACACACACACATAAACACACACA CACACACACA 1564 8 8.. .77 AGT---TCATCCCAGCACAAGCACACACACACACA--CACAAACA CACACACACA 1564

8 . . 6 AGT- - -TCATCCCAGCACAAGCACACACACACACA- -CACAAACA CACACACACA 1564

8 . 8 AGT TCATCCCAGCACAAGCACACACACACACA- -CACAAACA CACACACACA 1564

8 . 5 AGT- - -TCATCCCAGCACAAGCACACACACACACA- -CACAAACA CACACACACA 1567

8 . 2 TGCCAGTGATCTCAGTGGAAGTGCCGACCCACACGTAGGGGAGAA AAACACACA 1580 4 4.. .11 aa AATCTAGAAGACCTATTGGCTGAGAGACCTGCAGCCTCATAGTTCATTAGCTCTC-CATA 1566

* * * ** * * 8 . 9 AACACACATACTCACAC GGTTTCA- -TAGGTAAAGATTTCTTCCCTGA 1622

8 . 10 CACACACACACACACAC GGTTTCA- -TAGGTAAAGATTTCTTCCCTGA 1622

8 . 3 CACACACA CAC - -GGCTTCA- -TAGGTAAAGATTTCTTCCCTGA 1892

8 . 11 CACACACA CAC GGCTTCA- -TAGGTAAAGATTTCTTCCCTGA 1902

4 . 2_a AACACACTCACACACACACACGCACAC- -GGTTTCC- -TAGGTAAAGATTTCTTCCCTGC 1600 4 . 5 AACACAATCACACACACACACTCACAC- -GGTTTCC- -TACGTAAAGATTTCTTCCCTGC 1623

4 . 3 AACACACTCACACACACACACGCACAC- -GGTTTCC- -TAGGTAAAGATTTCTTCCCTGC 1622

4 . 2_b AACACACTCACACACACACACGCACAC- -GGTTTCC- -TAGGTAAAGATTTCTTCCCTGC 1622 4 . 4 AACACACTCACACACACACACGCACAC- -GGTTTCC- -TAGGTAAAGATTTCTTCCCTGC 1622 4 4. .1l_bb AACACACTCACACACACACACACACACACGGTTTCC--AAGGTAAAGATTTCTTCCCTGC 1622 8 . 1 CACACACACACACACACAGACACACACAGGGTTTCA- -TAGGTAAAGATTTCTTCCCTGA 1622

8 . 7 CACACACACACAGAGAGAGATACACACACGGTTTCA- -TAGGTAAAGATTTCTTCCCTGA 1622

8 . 6 CACACACACACACACACAGACACACACACGGTTTCA- -TAGGTAAAGATTTCTTCCCTGA 1622

8 . 8 CACACACACACACACACAGACACACACACGGTTTCA- -TAGGTAAAGATTTCTTCCCTGA 1622 8 8. .55 CACACACACACAGAGAGAGATACACACACGGTTTCA- -TAGGTAAAGATTTCTTCCCTGA 1625

8 . 2 CACACACACACACACAC GGTTTCA- -TAGGTAAAGATTTCTTCCCTGA 1626

4 . l_a GCAACTCTCACATGAAATGAAGTCAGTGGTGTTTCAAGTGCTTGAAACCCTCTTTACT-C 1625 ** * * *** * ** **** ** 8 8. .99 CATTCTTTTACCTAAAATAAG GCAACTGTGTGGCCACTGTCCCAACCCGGTTACCAT 1679

8 . 10 CATTGTTTTACCTAAAATAAG GCAACTGTGTGGCCACTGTCCCAACCCGGTTACACT 1679

8 . 3 CATTGTTTTACCTAAAATAAG GCAACTGTGTGGCCACTGTCCCAACCTGGTTACACT 1949

8 . 11 CATTGTTTTACCTAAAATAAG- - -GCAACTGTGTGGCCACTGTCCCAACCTGGTTACACT 1959

4 . 2_a CATTGCTTTACCTAAAATAAG- - -GCAACTGTGAGGCCACTGTCCCAACCCGGTTACACT 1657 44. .55 CATTGCTTTACCTAAAATAAG- - -GCAACTGTGTGGCCACTGTCCCAACCCGGTTACACT 1680

4 . 3 CATTGCTTTACCTAAAATAAG GCAACTGTGAGGCCACTGTCCCAACCCGGTTACACT 1679

4 . . 2_b CATTGCTTTACCTAAAATAAG GCAACTGTGAGTCCACTGTCCCAACCCGGTTACACT 1679 4 , . 4 CATTGCTTTACCTAAAATAAG- - -GCAACTGTGAGGCCACTGTCCCAACCCGGTTACACT 1679

4 , . l_b CATTGCTTTACCTAAAATAAG- - -GCAACTGTGTGGCCACTGTCCCAACCCGGTTACACT 1679 88...11 CATTCTTTTACCTAAAATAAG GCAACTGTGCGGCCACTGCCCAAACCCGGTTACACT 1679

8 . . 7 CATTCTTTTACCTAAAATAAG- - -GCAACTGTGTGGCCACTGTCCCAACCCGGTTACACT 1679

8 . . 6 CATTCTTTTACCTAAAATAAG GCAACTGTGTGGCCACTGTCCCAACCCGGTTACACT 1679

8 . . 8 CATTCTTTTACCTAAAATAAG- - -GCAACTGTGTGGCCACTGTCCCAACCCGGTTACACT 1679

8 . . 5 CATT-CTGTACCTAAAATAAG GCAACTGTGTG-CCACTGTCCCAACCCG-TTACACT 1679 8 8.. .22 CATTGTTTTACCTAAAATAAG- - -GCAACTGTGTGGCCACTGTCCCAACCCGGTTACACT 1683

4 . . l_a TACTTCTAAATGTGAATTAATTATGCAAATTTACTAGCAGTTGCTAGACCT- -CAAAAGC 1683 * * * * * ** *_** **** * * ** * * *** *

8 . . 9 CATATTATATGTGCCTATCATCCTGAGGAGTAATTT GATGAAGGTGTTTTAGAAGT 1735 8 8.. .1100 CATATTACATGTGTCTATCAGCCTGAGGAGTAGTTT GATTCAGGTGTTCTAGAAGT 1735

8 . . 3 CATATTACATCTGCCTATCATCCTGAGGAGTAATGT GATTCAGGTGTTCTAGAAGT 2005

8 . . 11 CATATTACATCTGCCTATCATCCTGAGGAGTAATGT GATTCAGGTGTTCTAGAAGT 2015

4 . 2_a CCTATTATATGTGCCTATCATCCTGAGGAGTAATTT GATTCAGGTGTTCTGGAAGT 1713 4 . . 5 CCTATTATATGTGCCTATCATCCTGAGGAGTAATTT GATTCAGGTGTTCTGGAAGT 1736 4 4.. ,33 CCTATTATATGTGCCTATCATCCTGAGGAGTAATTT GATTCAGGTGTTCTGGAAGT 1735

4 . , 2_b CCTATTATATGTGCCTATCATCCTGAGGAGTAATTT GATTCAGGTGTTCTGGAAGT 1735 4 . , 4 CCTATTATATGTGCCTATCATCCTGAGGAGTAATTT GATTCAGGTGTTCTGGAAGT 1735

4 . , l_b CCTATTATATGTGCTTATCATCCTGAGGAGTAATCT GATTCAGGTGTTCTGGAAGT 1735 8 .. 1 CATATTATATGTGCCTATCACCCTGAGGAGTAATTT GATTCAGGTGTTCTAGAAGT 1735 8 8.. .77 CATATTATATGTGCCTATCACCCTGAGGAGTAATTT GATTCAGGTGTTCTAGAAGT 1735

8 . , 6 CATATTACATGTGTCTATCAGCCTGAGGAGTAATTT GATTCAGGTGTTCTAGAAGT 1735

8 . , 8 CATATTACATGTGTCTATCAGCCTGAGGAGTAATTT GATTCAGGTGTTCTAGAAGT 1735

8 . , 5 CATATTATATGTGCCTATCACCCTGAGGAGTAATTT GATTCAGGTGTTCTAGAAGT 1735

8 . . 2 CATATTACATGTGTCTATCAGCCTGAGGAGTAGTTT GATTCAGGTGTTCTAGAAGT 1739 4 4.. ,11 aa AAAATAATCAGGCATTATTCTACTAAGTATTGGTCTCCATAACTCCTCTATTTTCTTTAG 1743 8 - 9 CATGATGTGGACTGTGTCTGTTGAATTCCCAGCGATGCAAGGGGACACACCCTGTGACTC 1795

8.10 CATGATGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCAAGGGGACACACCCTGTGACTC 1795 8.3 CATGATGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCAAGGGGACACACCCTGTGACTC 065

8.11 CATGATGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCAAGGGGACACACCCTGTGACTC 2075 4.2_a CATGCTGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCCAGGGGACACACCCTGTGACTC 1773

4.5 CATGCTGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCAAGGGGACACACCCTGTGACTC 1796

4.3 CATGCTGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCCAGGGGACACACCCTGTGACTC 1795 4.2_b CATGCTGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCCAGGGGACACACCCTGTGACTC 1795

4.4 CATGCTGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCCAGGGGACACACCCTGTGACTC 1795 4.1_b CATGATGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCAAGGGGACACACCCTGTGACTC 1795

8.1 CATGATGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCAAGGGGACACACCCTGTGACTC 1795

8.7 CATGATGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCAAGGGGACACACCCTGTGACTC 1795

8.6 CATGATGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCAAGGGGACACACCCTGTGACTC 1795

8.8 CATGATGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCAAGGGGACACACCCTGTGACTC 1795 8.5 CATGATGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCAAGGGGACACACCCTGTGACTC 1795

8.2 CATGATGTGGGCTGTGTCTGTTGAATTCCCAGCGATGCAAGGGGACACACCCTGTGACTC 1799 4.1_a GAAAAGTTAGTCTAAGACATTTGGCATAAAGGCTATGCCAAAGCTTTGGTGGGGTCAGCC 1803

* * * ** * * *** * ** **** * * ** * * 8.9 ATTCCTTAATTGAGTGCTGATATTTGATTGGTTTATTGCCCACCTTATGTGCGGGTGGGG 1855

8.10 ATTCCTTAATTGAGTGCTGATATTTGATTGGTTTATCGCGCACCTGATGGGTGGGTGGGG 1855

8.3 ATTCCTTAATTAAATGCTGACATTTGATTGGCTTATCGCGCACCTGATGAGTGGGTGAGG 2125

8.11 ATTCCTTAATTAAATGCTGATATTTGATTGGTTTATCGCGCACCTGATGAGTGGGTGAGG 2135 4.2_a CTTCCTGAATTGAGTGCTGATATTTGATTGGCTTATCGCGCACCTGATGAGTAGGTGGGG 1833 4.5 CTTCCTGAATTGAGTGCTGATATTTGATTGGCTTATCGCGCACCTGATGAGTGGGTGGGG 1856

4.3 CTTCCTGAATTGAGTGCTGTTATTTGATTGGCTTATCGCGCACCTGATGAGTGGGTGGGG 1855 4.2_b CTTCCTGAATTGAGTGCTGATATTTGATTGGCTTATCGCGCACCTGATGAGTGGGTGGGG 1855

4.4 CTTCCTGAATTGAGTGCTGATATTTGATTGGCTTATCGCGCACCTGATGAGTGGGTGGGG 1855 4. l_b CTTCCTGAATTGAGTGCTGATATTTGATTGGCTAATCGCGCACCTGATGAGTGGGTGGGG 1855 8.1 ATTCCTTAATTGAGTGCTGATATTTGATTGTTTTATCGCGCACCTGATGGGTGGGTGGGG 1855

8.7 ATTCCTTAATTGAGTGCTGATATTTGATTGGTTTATCGCACACCTGATGGGTGGGTGGGG 1855 8.6 ATTCCTTAATTGAGTGCTGATATTTGATTGGTTTATCGCACACCTGATGGGTGGGTGGGG 1855

8.8 ATTCCTTAATTGAGTGCTGATATTTGATTGGTTTATCGCACACCTGATGGGTGGGTGGGG 1855

8.5 ATTCCTTAATTGAGTGCTGATATTTGATTGGTTTATCGCACACCTGATGGGTGGGTGGGG 1855 8.2 ATTCCTTAATTGAGTGCTGATATTTGATTGGTTTATCGCGCACCTGATGGGTGGGTGGGG 1859

4.1_a AGGAAGGATTCGTGGGGGTCTCCTTGAAAATACTGCAATA-ATCTAAGAAATCTTCAACC 1862

* * * **** * ** *

8.9 TGTTCGCTCTTGGTGCGGGTGAGTTATGTAAGGGCTGATTTGGCCAGAGAACTCGTTATT 1915 8.10 TGTTCGCGGTTGGTGGGGGTGAGTTATATAAGGGCTGATGCGGCCAGAGAGCTCGTCATT 1915

8.3 TGTTCGCCGTTGGTGGGGGTGAGTTATATAAGGGCTGATGCGGCCAGAGAGCTCGTCATT 2185 8.11 TGTTCGCCGTTGGTGCGGGTGAGTTATATAAGGGCTGATGCGGCCAGAGAGCTCGTCATT 2195 4.2_a TGTTCGCGGTTGGTGGGGGTGACTTACAGAAGGGCTGATGTGGCCAGAGAGCTCGTCATT 1893

4.5 TGTTCGCGGTTGGTGGGGTTGACTTACAGAAGGGCTGATGCG-CCAGAGAGCTCGTCATT 1915 4.3 TGTTCGCGGTTGGTGGGGGTGACTTATAGAAGGGCTGATGCGGCCAGAGAGCTCGTCATT 1915

4.2_b TGTTCGCTGTTGGTGGGGGTGACTTACAGAAGGGCTGATGCGGCCAGAGAGCTCGTCATT 1915

4.4 TGTTCGCGGTTCGTGGGGGTGACTTACAGAAGGGCTGATGCGGCCAGAGAGCTCGTCATT 1915 4. l_b TGTTCGCGGTTGGTGTGGGTGAGTTATAGAAGGGCTGATGCGGCCAGAGAGCTCGTCATT 1915

8.1 TGTTCGCGGTTGGTGGGGGTGAGTTCTATAAGGGATGATGCGGCCAGAGAGCTCGTCATT 1915 8.7 TGTTCGCGGTTGGTGGGGGTGAGTTATATAAGGGCTGATGCGGCCAGAGAGCTCGTCATT 1915

8.6 TGTTCGCGGTTGGAGGGGGTGAGTTATATAAGGGCTGATGCGGCCAGAGAGCTGGTCATT 1915 8.8 TGTTCGCGGTTGGAGGGGGTGAGTTATATAAGGGCTGATGCGGCCAGAGAGCTGGTCATT 1915

8.5 TGTTCGCGGTTGGTGGGGGTGAGTTATATAAGGGCTGATGCGGCCAGAGAGCTCGTCATT 1915

8.2 TGTTCGCGGTTGGTGGGGGTGAGTTATATAAGGGCTGATGCGGCCAGAGAGCCCGTCATT 1919 4.1 a TATTGCCCCTCAGTACTGTTG-GTCCCCTGTACTTGACTTTTCCCCTTAAGTTTG--ATT 1919 8.9 TGAAGACTCTCTCGGAAGAGATAGCGTTTTTCTGCAACCTACGGTCCCAGCAGAAAAACC 1975

8 .10 TGAAGACTCTCTCGGAAGAGATAGCATCTTTCTGCAACCTGCGGTCCCAGCCGAAAAACC 1975

8 .3 TGAAGACTCTCTCGGAAGAGATAGAGTCTTTCTGCAACATAAGGTCCCAGCCGAAAAACC 2245

8 .11 TGAAGACTCTCTCGGAAGAGATAGCGTCTTTCTGCAACATAAGGTCCCAGCCGAAAAACC 2255

4 .2 a TGAAGACTCTCTCGGAAGGGATAGCGTCTTTCTGCAACCTGTGGTCCCAGCAGACAAACC 1953

4 .5 TGAAGACTCTCTCGGAAGGGATAGCGTCTTTCTGCAACCTGCGGTCCCAGCAGAAAAACC 1975

4 .3 TGAAGACTCTCTCGGAAGGGATAGCGTCTTTCTGCAACCTGCGGTCCCAGCAGAAAAACC 1975

4 .2 b TGAAGACTCTCTCGGAAGGGATAGCGTCTTTCTGCAACCTGCGGTCCCAGCAGAAAAACC 1975

4 .4 TGAAGACTCTCTCGGAAGGGATAGCGTCTTTCTGCAACCTGCGGTCCCAGCAGACAAACC 1975 4 4. .11_bb TGAAGACTCTCTCGGAAGAGATAGCGTCTTTCTGCAACCTGCGGTCCCAGCAGAAAAACC 1975

8 .1 TGAAGACTCTCTCGGAAGAGATAGCGTCTTGCTGCAACCTGCGGTCCCAGCAGAAAAACC 1975

8 .7 TGAAGACTCTCTTGGAAGAGATAGCGTCTTGCTGCAACCTGCGGTCCCAGCAGAAAAACC 1975

8 .6 TGAAGACTCTCTCGGAAGAGATAGCGTCTTGCTGCAACCTGCGGTCCCAGCAGAAAAACC 1975

8 .8 TGAAGACTCTCTCGGAAGAGATAGCGTCTTGCTGCAACCTGCGGTCCCAGCAGAAAAACC 1975 8 8. .55 TGAAGACTCTCTTGGAAGAGATAGCGTCTTGCTGCAACCTGCGGTCCCAGCAGAAAAACC 1975

8 .2 TGAAGACTC GGAAGAGATAGCGTCTTTCTGCAACCTGCGGTCCCAGCCGAAAAACC 1975

4 . ι_a CCATTTCCTAATATTATCCTTCCCTCTTCCTCCTCAGCAACTAGTCTTCTAAATTAGAAC 1979 * * * * * ** * *** * * * 8 8. .99 TTGTGATCCTTGTTGCGGGCGACATG 2001

8 .10 CTGTGATCCTTGTTCCGGGCGACATG 2001

8 .3 TTGTGATCCTTGTTCCGGGCGACATG 2271

8 .11 TTGTGATCCTTGTTCCGGGCGACATG 2281

4 .2 a TTGTGATCCTTGTTCCAGTCGACATGGAGGACGACTCACTCTACTTGGGAGGTGAGTGGC 2013 4 4.. .55 TTGTGATCCTTGTTCCAGTCGACATG 2001

4 .3 TTGTGATCCTCGTTCCAGTCGACATG 2001

4 .2 b TTGTGATCCTCGTTCCAGTCGACATG 2001

4 .4 TTGTGATCCTTGTTCCAGTCGACATG 2001

4 .1 b TTGTGATCCTTGTTCCAGTCGACATG 2001 8 8. .11 TTGTGATCCTTGTTGCGGGCGACATG 2001

8. .7 TTGTGATCCTTGTTGCGGGCGACATG 2001

8. .6 TTGTGATCCTTGTTGCGGGCGACATG 2001

8. .8 TTGTGATCCTTGTTGCGGGCGACATG 2001

8. .5 TTGTGATCCTTGTTGCGGGCGACATG 2001 8 8.. .22 TTGTGATCCTTGTTCCGGGCGACATG 2001

4. .l_a TTAAACACAATG AGCAGATATG 2001

* * * * ** ***

8 8.. .99 8 8.. .1100 8 8.. .33 8 8.. .1111

4. ,2 a AGTTCAACCACTTTTCAAAACTCACATCTTCTCGGCCAGATGCAGCTTTTGCTGAAATCC 2073

4. .5

4. .3

4. ,2_b

4. .4

4. ,1 b

8. .1

8. ,7

8. ,6

8. 8

8. 5

8. .2

4. .1 a 8.9

8 .10

8 .3

8 .11

4 .2_a AGCGGACTTCTCTCCCTGAGAAGTCACCACTCTCATGTGAGACCCGTGTCGACCTCTGAG 2133

4 .5

4 .3

4 .2_b

4 .4

4 .l_b

8 .1

8 .7

8 .6

8 .8

8 .5

8 .2

4 . l_a

8 .9

8 .10

8 .3

8 .11

4 .2_a ATGATTTGGCTCCTGTGGCAAGACAGCTTGCTCCCAGGGAGAAGCTTCCTCTGAGTAGCA 2193

4 .5

4 .3

4 .2_b

4 .4

4. ,l_b

8. .1

8, .7

8 .6

8. .8

8. .5

8. .2

4. .ι_a

8. .9

8. .10

8. ,3

8. .11

4. .2_a GGAGACCTGCTGCGGTGGGGGCTGGGCTCCAGAATATG 2231

4. 5

4. .3

4. 2_b

4. ,4

4. l_b

8. 1

8. .7

8. ,6

8. 8

8. 5

8. 2

4. 1 a

HDUB4.6 putative promoter sequence upstream of initiation ATG gcatgactgg cagacagctt atcgattggg ctcccctcaa aatcggttat gagcattcaa gcacaccgat gcccaggtcc cggctgcagg aataagaccc tccagggtct tgtgtgaagc ctcggcatct gcattgctca tgcttctggg gatcattctc ctgaaaatgg tggctccttt ctccctgtgg agcatctttc taagcagtgc tcttttcttc ccccaggaca ctttacatcc ggcacaggaa gccttctgat ggagcacacc tggcccatga aaagacaagg gaaagaaacg gggccaaagg tcacagtcct ctcatcccat catcctcctt aaaatcatcc taatttcatg ggccctgaag ccagggctgt ttctttacac ctagaggcct tggcgccggg cctcaattcc gccctgttcc ttaccgtcta agacatgttg ggaaaatccc tagagccagg atcttcattc ctgctaagcc agacagccgg aagacacacc caaattctgt ccctcttact tcagggaaca tgtccacttt cggcagcatt acaattttgg caccaaatgt gctaactgca attccaccat acaatgcgta actggaaatg gaggcaacat ctccgatcct gaacgatcga tgcgagaatc caggatatgc acggcttatt ttggcctttt cccactgaaa caagggccag tattaaaaat ggcacgctat cctctgtttc actccctgct tttaaacgtc tccgatgttt ctccctgaga cagggcctca cttccgtcag ccgggctttt ccacggtata attttccttg tttgcttttg tccaaattag aactttttat ttcacctcta ggaaacgttg atccattatc acatacgtat ggaaatatta tcacacatgc tgtgagatac gttgttttta ttttcatcaa ttctttaata aacaaacggt tatagctggg ataccttctg agttctcaag ttttttgttt cgtgttttct taaactgccg tcgcacgtcc gaaaccgctc actatgcagt gtcatgaccg tctctctttt ctggcaaaca taaatttggg gattgtcatc aattagtctc tcggggattg catgatttcc ccaaaggctt tcacagtcta ctttgtgcac tgagtatctc ttcaaacttc agtgcatgtt tctaccattt catgctttct tatttggcaa tctagcttcc acaagagcat ttcatgcaaa gacttgtctt gttctccact ggcaggtaat ttcactcaga tagagaatca ataggctcaa cgtggaaagg ttatcgctgg aaggtctgtt tgattccacg gatctctcct ttctcattag ggaagaaaat acgctgtgct aaatactata cttcattgac tattctcagg tcagaaagcg cactttcgac ttcttgtctt tccgtcgctg agaggatgat ggcagctgcc aaaagtacat acttggaagt tcatcgcaga aaaaacacac acacacacgc gcccccccca cacacacaca cacgaacaca atcacacaca cacacactca cacggtttcc tacgtaaaga tttcttccct gccattgctt tacctaaaat aaggcaactg tgtggccact gtcccaaccc ggttacactc ctattatatg tgcctatcat cctgaggagt aatttgattc aggtgttctg gaagtcatgc tgtgggctgt gtctgttgaa ttcccagcga tgcaagggga cacaccctgt gactccttcc tgaattgagt gctgatattt gattggctta tcgcgcacct gatgagtggg tgtggtgttc gcggttggag ggggtgactt acagaagggc tgatgcggcc agagagctcg tcatttgaag actctctcgg aagggatagc gtctttctgc aacctgcggt cccagcagaa aaaccttgtg atccttgttc cagtcgacat 9

HDUB4.7 putative promoter sequence upstream of initiation ATG tcctcagcgt cggtttttag gcctggcata agctgtttga aacccaggaa cgtaccccac ccatcatctt tggcctagtt aacacctccc ctccgtgtgt ggtggtttgg agaacctgct ttttcctcat cccactgatc ccaaacccag gacaccctac agctgctgac caggattaaa cctaatggag atttaatgcc attaaatcag aaga'aattct gattctcagg gactgacatt cattcactta catacttgca gagtcggcca ggtgtgttgg ctcacacctg taatcccagc actttgggaa gccgaggtgg gtggatcacg aggtcaagaa ttcgagacca tcctggccaa catggtgaaa ccccgtctct actaaaaata caaaaattaa ctggtgtagc tgtgcgtgcc tgtaatccca gctactcagg aggctgaggc aggcgatttg cttgaacctg ggaggtggag gttgcagtga gccaagatta tgccattgca ctccagcctg ggcaacagag cgagactctc agaaaacaaa aaacccaaaa acttgcagag tgaatttagg aaaccatgaa gtacacagtt tgatccaatg ccttcctttt tctctttctc aaatattttg agccaggtac tatcctagac tgtcttgtga tatttacaat ctaggagaag gcaggagaga gaactaagaa cagagagcat gttctgagat gtctgctgtg tttgcaggta ccttccctca atttccctac tcactggcca tgctggaaag caggtcttgg cgctatattt ataccatggt acttcccctc cctatactca attggttggc cagaagccca attgtcactc tctctctctg tctccctctc gctccctccc tccctccctc cctccctccc tctccaagat atccagtaac tgactgatca gctgggggtg ggctctgctg gctgccaaga tgggccacca gcaaaaaggg aaaattggtt gtgagtgaga agaagagata agaaattcca cagggctgat aagaaagacc atgggcttcc aggcgcggtg tttcacgcct gtaatcccag cacttgggag gccaggatgg tcggatttgg caatctagct tccacaagag catttcacgc aaagacttgt cttgttctcc actggcaggt aatttcactc ggatagagaa tcaataggct caacgtggaa aggttatcgc tggaaggtct gtttaattcc acggatctct cctttctcat tagggaagaa aatacgctgt gctaaatact atacttcatt gactattctc aggtcagaaa gcgcactttc gacttcttgt ccttccgtcg ctgagaggat gatggcagct gccaaaagta catacttgga agttcatccc agcacaaaca cacacacaca cacgcccccc cacacacaca cacacaaaca cactcacaca cacacacgca cacggtttcc taggtaaaga tttcttccct gccattgctt tacctaaaat aaggcaactg tgaggccact gtcccaaccc ggttacgctc ctattatatg tgcctatcat cctgaggagt aatttgattc aggtgttctg gaagtcatgt tgtgggctgt gtctgttgaa ttcccagcga tgccagggga cacaccctgt gactccttcc tgaattgagt gctgatattt gattggctta tcgcgcacct gatgagtggg tggggtgttc gcggttggtg ggggtgactt acagaagggc tgatgcggcc agagagctcg tcatttgaag actctctcgg aagggatagc gtccttctgc aacctgcggt cccagcagac aaaccttgtg atccttgttc cagtcgacat g

HDUB4.8 putative promoter sequence upstream of initiation ATG

CAGGGCTCCG TAGAACCACA GAATCTTGGG CGCAACCCTG CTCAAGCACC CAAATGTGCA TACGAACAGG GTCTCCGTGT GACGTGTGTG AAAACTACAG TGTGATGAGC ATGACTGGCA GACAGCTTAT CGATTGGGCT CCCCTCAAAA TCGGTTATGA GCATTCAAGC ACACCGATGC CCAGGTCCCG GCTGCAGGAA TAAGACCCTC CAGGGTCTTG TGTGAAGCCT CGGCATCTGC ATTGCTCATG CTTCTGGGGA TCATTCTCCT GAAAATGGTG GCTCCTTTCT CCCTGTGGAG CATCTTTCTA AGCAGTGCTC TTTTCTTCCC CCAGGACACT TTACATCCGG CACAGGAAGC CTTCTGATGG AGCACACCTG GCCCATGAAA AGACAAGGGA AAGAAACGGG GCCAAAGGTC ACAGTCCTCT CATCCCATCA TCCTCCTTAA AATCATCCTA ATTTCATGGG CCCTGAAGCC AGGGCTGTTT CTTTACACCT AGAGGCCTTG GCGCCGGGCC TCAATTCCGC CCTGTTCCTT ACCGTCTAAG ACATGTTGGG AAAATCCCTA GAGCCAGGAT CTTCATTCCT GCTAAGCCAG ACAGCCGGAA GACACACCCA AATTCTGTCC CTCTTACTTC AGGGAACATG TCCACTTTCG GCAGCATTAC AATTTTGGCA CCAAATGTGC TAACTGCAAT TCCACCATAC AATGCGTAAC TGGAAATGGA GGCAACATCT CCGATCCTGA ACGATCGATG CGAGAATCCA GGATATGCAC GGCTTATTTT GGCCTTTTCC CACTGAAACA AGGGCCAGTA TTAAAAATGG CACGCTATCC TCTGTTTCAC TCCCTGCTTT TAAACGTCTC CGATGTTTCT CCCTGAGACA GGGCCTCACT TCCGTCAGCC GGGCTTTTCT ACGGTATAAT TTTCCTTGTT TGCTTTTGTC CAAATTAGAA CTTTTTATTT CACCTCTAGG AAACGTTGAT CCATTATCAC ATACGTATGG AAATATTATC ACACATGCTG TGAGATACGT TGTTTTTATT TTCATCAATT CTTTAATAAA CAAACGGTTA TAGCTGGGAT ACCTTCTGAG TTCTCAAGTT TTTTGTTTCG TGTTTTCTTA AACTGCCGTC GCACGTCCGA AACCGCTCAC TATGCAGTGT CATGACCGTC TCTCTTTTCT GGCAAACATA AATTTGGGGA TTGTCATCAA TTAGTCTCTC GGGGATTGCA TGATTTCCCC AAAGGCTTTC ACAGTCTACT TTGTGCACTG AGTATCTCTT CAAACTTCAG TGCATGTTTC TACCATTTGA TGCTTTATTA TTTGGCAATC TAGCTTCCAC AAGAGCATTT CATGCAAAGA CTTGTCTTCT TCTCCACTGG CAGGTAATTT CACTTGGACA GAGAATCAAT AGGCTCAACG TGGAAAGGTT ATCGCTGGAA GGTCTGTTTG ATTCCACGGA TCTCTCCTTT CTCATTAGGG AAGAAAATAC GCTGTGCTAA ATACTATACT TCATTGACTA TTCTCAGGTC AGAAAGCGCA CTTTCGACTT CTTGTCCTTC CGTCGCTGAG AGGATGATGG CAGCTGCCAA AAGTACATAC TTGGAGGTTC ATCCCAGCAC AAACACACAC ACACACGCGC CCCCCCCACA CACACACACA CGAACACAAT CACACACACA CACTCACACG GTTTCCTACG TAAAGATTTC TTCCCTGCCA TTGCTTTACC TAAAATAAGG CAACTGTGTG GCCACTGTCC CAACCCGGTT ACACTCCTAT TATATGTGCC TATCATCCTG AGGAGTAATT TGATTCAGGT GTTCTGGAAG TCATGCTGTG GGCTGTGTCT GTTGAATACC CAGCGATGCA AGGGGACACA CCCTGTGACT CCTTCCTGAA TTGAGTGCTG ATATTTGATT GGCTTATCGC GCACCTGATG AGTGGGTGGG GTGTTCGCGG TTGGTGGGGG TGACTTACAG AAGGGCTGAT G HDUB4.9 putative promoter sequence upstream of initiation ATG gcatctttct agtcagcgct cttttcttcg cccaggacac tttacatccg gcacacgaag ccttctgatg gagcacacct ggcccatgaa aagccaaggg aaagaaacgg ggccaaaggt cacagtcctc tcctcccatc atcctcctta aaatcatcct aatttcctgg ccctgaagcc agggctgttt ctttacacct agaggccttg gcgccgggcc tcaattccgc cctgttcctt accgtctaag acatgttggg aaaatcccta gagccaggat cttcattcct gctaagccag acagccggaa gacacaccca aattctgtcc ctcttacttc agggaacatg tccactttcg gcagcattac aattttggca ccaaatgtgc taactgcaat tccaccatac aatgcctaac tggaaatgga ggcaacatct ccgatcctga acgatcgatg cgagaatcca ggatatgcac ggcttatttt ggccttttcc cactgaaaca agggccagta ttaaaaatgg cacgctatcc tctgtttcac tccctgcttt taaacgtctc cgatgttgct ccctgagaca ggacctcact tccgtcagcc gggcttttct acggtataat tttccttgtt tgcttttgtc caaattagaa ctttttattt catctctagg aaacgttgat ccattatcac atacgtatgg aaatattatc acacatgctg tgagatacgt tgtttttatt ttcatcaatt ctttaataaa caaaaggtta tagctgggat accttctgag ttctcaagtt ttttgtttcg tgttttctta aactgccgtc gcacgtccga aaccgctcac tatgcagtgt catgaccgtc tctcttttct ggcaaacata aatttgggga ttgtcatcaa ttagtctctc ggggattgca tgatttcccc aaaggctttc acagtctact ttgtgcactg agtatctctt caaacttcag tgcatgtttc tacaatttga tgctttatta tttggcaatc tagcttccac aagagcattt catgcaaaga cttgtcttgt tctccactgg caggtacttt cactcggaca gagaatcaat aggctcaacg tggaaaggtt ttcgctggaa ggtctgtttg attccacgga tctctccttt ctcattaggg aagaaaatac actgtgctaa atactatact tcattgacta ttctcaggtc agaaagcgca ctttcgactt cttgtccttc cgtcgctgag aggatgatgg cagctgccaa aagtacatac ttggaagttc atcccagcac aaacacacac acacgcgccc ccccacacac acacacaaac acaatcacac acacacacaa tcacacggtt tcctaggtaa agatttcttc cctgccatgg ctttacctaa aataaggcaa ctgtgtgacc actgtcccaa cccggttaca ctcctattat atgtgcctat catcctgagg agtaatttga ttcaggtgtt ctggaagtca tgctgtggga tgtgtctgtt gaattcccag cgatgccagg gggacacacc ctgtgactcc ttcctgaatt gagtgctgat atttgattgg cttatcgcgc acctgatgag tgggtggggt gttcgcggtt ggtgggggtg acttacagaa gggctgatgc ggccagagag ctcgtcattt gaagactctc tcggaaggga tagcgtcttt ctgcaacctg cggtcccagc agaaaaacct tgtgatcctt gttccagtcg acatg

HDUB4.10 putative promoter sequence upstream of initiation ATG agcaagcttt ggaacagttg gtgaagcccg aagaactcaa tggagagaat gcctatcatt gtggtgtttg tctccagagg gcgccggcct ccaagacgtt aactttacac acctctgcca aggtcctcat ccttgtattg aagagattct ccgatgtcac aggcaacaag attgccaaga atgtgcaata tcctgagtgc cttgacatgc agccatacat gtctcagcag aacacaggac ctcttgtcta tgtcctctat gctgtgctgg tccacgctga gtggagttgt cacaacggac attacttctc ttatgtcaaa gctcaagaag gccagtggta taaaatggat gatgccgagg tcaccgccgc tagcatcact tctgtcctga gtcaacaggc ctacgtcctc ttttacatcc agaagagtga atgggaaaga catagtgaga gtgtgtcaag aggcagggaa ccaagagccc ttggcgcaga agacacagac aggcgagcaa cgcaaggaga gctcaagaga gaccacccct gcctccaggc ccccgagttg gacgagcact tggtggaaag agccactcag gaaagcacct tagaccactg gaaattcctt caagagcaaa acaaaacgaa gcctgagttc aacgtcagaa aagtcaaagg taccctgcct cccgacgtac ttgtgattca tcaatcaaaa tacaagtgtg ggatgaagaa ccatcatcct gaacagcaaa gctccctgct aaacctctct tcgtcgaccc cgacacatca ggagtccatg aacactggca cactcgcttc cctgcgaggg agggccagga gatccaaagg gaagaacaaa cacagcaaga gggctctgct tgtgtgccag tgatctcagt ggaagtaccg acccacacgt aggggtgcac acacacacgc acacacacag acacacacat aactacaccc agaagcgcgc acgcaaacac acacacaccc acacaaacac gaacaccgtc aatcctacat aaactaatga ggagcccaag tttctgtctc tacaacaggg acaactggat agtgatggct acatctcagg atgagcccgc atatgggaaa catcaagttt tggggtcgtg agtcttccga acctctggag ggactgtctg agtgtttgtg ttcatgatag gtgacattca gtgtgtattt ctgaatatga cctaccgacg tgtaggtttg cgtgtgaggt aattgcaggg gactcggttt cgtattttct cttggggtgt gtttcattcg tcagttgttg gtcggcatga gaaggtgaaa tgtggctcat gtgggacatc cgtggatcat tctcgccacc ttgaatagtg gaaactggaa tgcatttgga agagaagaac ggtgctcttc tttcttcccc gggctcgccg tttttacact ggttcctgaa tggacctcag gcgccctggg acttgtgctc ttgctggaac ccacataacg ccggaagcgg acagaccgac ttgcctgttt cacggtgccc gcttcccatg agtccaaacg gaaaattttc ccacgggcat gtaagtcatc tggaagtaag ctgtattgat aataaaggaa agcaaacaca ggagtgtgtg tattcaactg aaataaattc agaaagccct gaaatcaatc tcactgggtg tgtttaaaaa tggcatttgg ggaatttctg ggtcatttgt ccagctgcga aagctgcatc tctgaagcac agtccctgtc ccgcagtgag acttattgat ccgacgtggt gtttccgtgg aaatgattgt gggaaatggc cccttccttt tctctatttg ctgattagac ttcatggtcc ctttctcgtc aggtacagtg atcaaagttg accagcccca gaggaaagct gcccagggca caactcaggg ctccgtagaa ccacagaatc ttgggcgcaa ccctgctcaa gcacccaaat g

HDUB4.11 putative promoter sequence upstream of initiation ATG cagcaagctt tggaacagtt ggtgaagccc gaagaactca atggagagaa tgcctatcat tgtggtgttt gtctccagag ggcgccggcc tccaagacgt taactttaca caactctgcc aaggtcctca tccttgtatt gaagagattc cccgatgtca caggcaacaa aattgccaag aatgtgcaat atcctgagtg ccttgacatg cagccataca tgtctcagca gaacacagga cctctcgtct atgtcctcta tgctgtgctg gtccacgctg ggtggagttg tcacaacgga cattactcct cttatgtcaa agctcaagaa ggccagtggt ataaaatgga tgatgccgag gtcaccgcct ctagcatcac ttctgtcctg agtcaacagg cctacgtcct cttttacatc cagaagagtg aatgggaaag acacagtgag agtgtgtcaa gaggcaggga accaagagcc cttggcgtag aagacacaga caggcgagca acgcaaggag agctcaagag agaccacccc tgcctccagg cccccgagtt ggacgagcac ttggtggaaa gagccactca ggaaagcacc ttagaccact ggaaattcct tcaagagcaa aacaaaacga agcctgagtt caacgtcaga agagtcgaag gtacggtgcc tcccgacgta cttgtgattc atcaatcaaa atacaagtgt cggatgaaga accatcatcc tgaacagcaa agctccctgc taaacctctc ttcgacgacc ccgacagatc aggagtccat gaacactggc acactcgctt ccctacgagg gaggaccagg agatccaaag ggaagaacaa acacagcaag agggctctgc ttgtgtgcca gtgatctcag tggaagtacc gacccacacg taggggtgca tacacacaca cacacacaca cacacacaca taactacacc cagaagcgcg cacgcaaaca cacacacacc cacacaaaca cgaacaccgt caatcctaca taaactaatg aggagcccaa gtttctgtct gtacaacagg gacaactgga tagagatggc tacatctcag gatgagcccg catatgggaa acatcaagtt ttggggtcgt gagtcttccg aacctctgga gggactgtct gagtgtttgt gttcatgata ggtgacattc agtgtgtatt tatgaatatg acctaccgac gtgtaggttt gcgtgtgagg taattgcagg ggactcggtt tcgtattttc tcttggggtg tgtttcattc gacagttgtt ggtcggcacg agaaggtgaa atttggctca tgtgggacat ccgtggatca ttctcgccac cttgaatagt ggaaactgga atgcatttgg aagagaagaa cggtgctctt ctttcttccc cgggctcgcc gtttttacac tagttcctga atggacctca ggcgccctgg gacttgtgct cttgctggaa cccacataac gccggaagca gacagaccga cttgcctgtt tcacggtgcc cgcttcccat gagtccaaac ggaaaatttt cccacgggca tgtaagtcat ctggaagtaa gctgtattga taataaagga aagcaaacac aggagtgtgt gtattcaaca gaaataaatt cagaaagccc tgaaatcaat ctcactgggt gtgtttaaaa atggcatttg gggaatttct gggtcatttg tccagctgcg aaagctgcat ctctgaagca cagtccctgt cccgcagtga gacttattta tccgacgtgg tgtttccgtg gaaatgattg tgggaaatgg ccccttcctt ttctctattt gctgactaga cttcatggtc cctttctcgt caggtacagt gatcaaagtt gaccaacccc agaggaaagc tgcccagggc acaactcagg gctccataga accacagaat cttgggagca accctgctca agcacccaaa tg

Claims

What is claimed is:

1. An isolated polynucleotide encoding a human deubiquitinating protease selected from the group consisting of hDUB 4.1a, hDUB 4.1b, hDUB 4.2a, hDUB 4.2b, hDUB 4.3, hDUB 4.4, hDUB 4.5, hDUB 4.6, hDUB 4.7, hDUB 4.8, hDUB 4.9, hDUB 4.10, hDUB 4.11, hDUB 8.1, hDUB 8.2, hDUB 8.3, hDUB 8.5, hDUB 8.6, hDUB 8.7, hDUB 8.8, hDUB 8.9, hDUB 8.10, and hDUB 8.11.

2. A polypeptide encoding a human deubiquitinating protease selected from the group consisting of hDUB 4.1a, hDUB 4.1b, hDUB 4.2a, hDUB 4.2b, hDUB 4.3, hDUB 4.4, hDUB

4.5, hDUB 4.6, hDUB 4.7, hDUB 4.8, hDUB 4.9, hDUB 4.10, hDUB 4.11, hDUB 8.1, hDUB 8.2, hDUB 8.3, hDUB 8.5, hDUB 8.6, hDUB 8.7, hDUB 8.8, hDUB 8.9, hDUB 8.10, and hDUB 8.11.

3. A method of using a polynucleotide according to claim 1, wherein the polynucleotide is used in an assay to identify an inhibitor of a hDUB of claim 1.

4. A method of using a polypeptide according to claim 2, wherein the polypeptide is used in an assay to identify an inhibitor of a hDUB of claim 2.

5. A method of reducing inflammation by regulating proinflammatory cytokine signaling, by administering a compound capable of inhibiting a polypeptide according to claim 2.

6. A method of modulating an autoimmune disease by altering cytokine receptor signaling involved in lymphocytes proliferation, by administering a compound capable of inhibiting a polypeptide according to claim 2.

7. A method of modulating an immune reaction during infection, by administering a compound capable of inhibiting a polypeptide according to claim 2.

8. A method of reducing inflammation by regulating proinflammatory cytokine signaling, by administering a compound capable of altering regulation of transcription of a polynucleotide of claim 1.

9. A method of modulating an autoimmune disease by altering cytokine receptor signaling involved in lymphocytes proliferation, by administering a compound capable of altering regulation of transcription of a polynucleotide of claim 1.

10. A method of modulating an immune reaction during infection, by administering a compound capable of altering regulation of transcription of a polynucleotide of claim 1.

11. A method of identifying a modulator of a human deubiquitinating protease, wherein a compound is added to the reporter assay comprising a polynucleotide immediately 5' to a human deubiquitinating protease selected from the group consisting of hDUB 4.1a, hDUB 4. lb, hDUB 4.2a, hDUB 4.2b, hDUB 4.3, hDUB 4.4, hDUB 4.5, hDUB 4.6, hDUB 4.7, hDUB 4.8, hDUB 4.9, hDUB 4.10, hDUB 4.11, hDUB 8.1, hDUB 8.2, hDUB 8.3, hDUB 8.5, hDUB 8.6, hDUB 8.7, hDUB 8.8, hDUB 8.9, hDUB 8.10, and hDUB 8.11 operatively linked to a reporter gene, and the effect of the compound is determined.