FI72344B - Foerfarande foer spjaelkning av dubbelstraengat dna - Google Patents
Foerfarande foer spjaelkning av dubbelstraengat dna Download PDFInfo
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- FI72344B FI72344B FI853489A FI853489A FI72344B FI 72344 B FI72344 B FI 72344B FI 853489 A FI853489 A FI 853489A FI 853489 A FI853489 A FI 853489A FI 72344 B FI72344 B FI 72344B
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- dna
- stranded
- stranded dna
- cleavage site
- polymerase
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- 108020004414 DNA Proteins 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 19
- 102000053602 DNA Human genes 0.000 claims description 16
- 238000003776 cleavage reaction Methods 0.000 claims description 16
- 230000007017 scission Effects 0.000 claims description 16
- 239000012634 fragment Substances 0.000 claims description 12
- 108020004682 Single-Stranded DNA Proteins 0.000 claims description 6
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 claims description 4
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 claims description 4
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 4
- 230000001036 exonucleolytic effect Effects 0.000 claims description 4
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 4
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 4
- 230000000295 complement effect Effects 0.000 claims description 3
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 2
- 229930024421 Adenine Natural products 0.000 claims description 2
- 229960000643 adenine Drugs 0.000 claims description 2
- 229940104302 cytosine Drugs 0.000 claims description 2
- 239000002773 nucleotide Substances 0.000 claims description 2
- 125000003729 nucleotide group Chemical group 0.000 claims description 2
- 229940113082 thymine Drugs 0.000 claims description 2
- 239000001226 triphosphate Substances 0.000 claims description 2
- 235000011178 triphosphate Nutrition 0.000 claims description 2
- 125000002264 triphosphate group Chemical class [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 claims description 2
- 239000013615 primer Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 108060002716 Exonuclease Proteins 0.000 description 6
- 102000013165 exonuclease Human genes 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 108091008146 restriction endonucleases Proteins 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 101000976075 Homo sapiens Insulin Proteins 0.000 description 2
- RGWHQCVHVJXOKC-SHYZEUOFSA-J dCTP(4-) Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)C1 RGWHQCVHVJXOKC-SHYZEUOFSA-J 0.000 description 2
- HAAZLUGHYHWQIW-KVQBGUIXSA-N dGTP Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 HAAZLUGHYHWQIW-KVQBGUIXSA-N 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 238000009396 hybridization Methods 0.000 description 2
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108091026890 Coding region Proteins 0.000 description 1
- 102000004594 DNA Polymerase I Human genes 0.000 description 1
- 108010017826 DNA Polymerase I Proteins 0.000 description 1
- 239000003155 DNA primer Substances 0.000 description 1
- 230000007018 DNA scission Effects 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 108010078233 Thymalfasin Proteins 0.000 description 1
- 102400000800 Thymosin alpha-1 Human genes 0.000 description 1
- 238000000211 autoradiogram Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- SUYVUBYJARFZHO-RRKCRQDMSA-N dATP Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 SUYVUBYJARFZHO-RRKCRQDMSA-N 0.000 description 1
- SUYVUBYJARFZHO-UHFFFAOYSA-N dATP Natural products C1=NC=2C(N)=NC=NC=2N1C1CC(O)C(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 SUYVUBYJARFZHO-UHFFFAOYSA-N 0.000 description 1
- NHVNXKFIZYSCEB-XLPZGREQSA-N dTTP Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)C1 NHVNXKFIZYSCEB-XLPZGREQSA-N 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- NZVYCXVTEHPMHE-ZSUJOUNUSA-N thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 description 1
- 229960004231 thymalfasin Drugs 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/61—Growth hormone [GH], i.e. somatotropin
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- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/655—Somatostatins
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/62—DNA sequences coding for fusion proteins
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- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/70—Vectors or expression systems specially adapted for E. coli
- C12N15/71—Expression systems using regulatory sequences derived from the trp-operon
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- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/26—Preparation of nitrogen-containing carbohydrates
- C12P19/28—N-glycosides
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- C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
- C07K2319/74—Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor
- C07K2319/75—Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor containing a fusion for activation of a cell surface receptor, e.g. thrombopoeitin, NPY and other peptide hormones
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Description
1 72344
Menetelmä kaksijuosteisen DNA:n pilkkomiseksi
Jakamalla erotettu patenttihakemuksesta 810 876 5 Yhdistelmä-DNA-tekniikan menetelmissä olennainen menetelmävaihe on kaksijuosteisen DNA:n pilkkominen. Tällöin tarvitaan usein sellaista pilkkomismenetelmää, jossa DNA saadaan katkaistuksi kontrolloidulla tavalla tietystä kohdasta. Restriktioentsyymit, joita DNA:n pilkkomiseen 10 yleisesti käytetään, pilkkovat DNA:n ainoastaan tietyistä katkaisukohdista (ts. tiettyjen nukleotidisekvenssien kohdalta) , jotka ovat kullekin entsyymille spesifisiä.
Esillä olevan keksinnön mukaisesti on kehitetty menetelmä, jolla kaksijuosteinen DNA voidaan pilkkoa mistä 15 kohdasta tahansa, myöskin siinä tapauksessa, että siinä ei ole minkään restriktioentsyymin katkaisukohtaa, mikä menetelmä on käyttökelpoinen mm. muodostettaessa trp-ope-roneja, joista on poistettu muita attenuaattorialueita kuin tähänastisella mutanttiselektiolla poistetut.
20 Keksinnön mukaista kaksijuosteisen DNA:n pilkkomis menetelmää voidaan soveltaa esim. polypeptidien valmistusmenetelmiin, joissa ekspressoidaan mainittua polypeptidiä koodaava rakennegeeni bakteerissa käyttäen bakteriaalista trp-promoottori-operaattori-järjestelmää (katso FI-patent-25 tihakemus 810876) sekä menetelmään ekspressioplasmin valmistamiseksi, jonka avulla voidaan ekspressoida hetorolo-ginen geeni (katso FI-patenttihakemus 85 3488) .
Keksinnön mukaiselle menetelmälle on tunnusomaista, että menetelmään kuuluu seuraavat vaiheet: 30 a) muutetaan kaksijuosteinen DNA yksijuosteiseksi katkaisukohdan molemmilta puolita; b) hybridisoidaan vaiheessa (a) muodostuneeseen yksijuosteiseen alueeseen yksijuosteisen DNA:n komplementaarinen primeeri, jonka 5'-pää sijaitsee vastapäätä ha-35 lutun katkaisukohdan viereistä nukleotidia; 2 72344 c) muodostetaan uudelleen se osa toisesta juos-teesta, joka on poistettu vaiheessa (a) ja joka sijaitsee 3'-suunnassa mainittuun primeeriin nähden, antamalla vaiheesta (b) saadun tuotteen reagoida DNA-polymeraasin kanssa 5 adeniinia, tymiiniä, guaniinia ja sytosiinia sisältävien deoksinukleotiditrifosfaattien läsnäollessa; ja d) lohkaistaan irti jäljelle jäänyt yksijuosteinen DNA-fragmentti, joka työntyy esiin halutusta katkaisukoh-dasta.
10 Keksinnön mukaisessa menetelmässä kaksijuosteinen DNA muutetaan yksijuosteiseksi halutun katkaisukohdan molemmilta puolilta, esim. antamalla kaksijuosteisen DNA:n reagoida lambda-eksonukleaasin kanssa. Synteettinen tai muu yksijuosteinen DNA-primeeri hybridisoidaan sitten muo-15 dostuneen yksijuosteisen fragmentin kanssa Watson-Crick- emäspariutumisen kautta, jolloin primeerisekvenssin täytyy olla komplementaarinen sen yksijuosteisen DNA:n sukleoti-din kanssa,joka sijaitsee sekvenssissä juuri ennen haluttua katkaisukohtaa. Primeerin 3'-päähän liitetään seuraavaksi 20 se osa alkuperäisestä kaksijuosteisesta DNA:sta, joka sijaitsi halutun katkaisukohdan edellä ja joka poistettiin ensimmäisessä vaiheessa, antamalla primeerin reagoida DNA-polymeraasin kanssa. Samanaikaisesti tai myöhemmin se osa ensimmäisestä juosteesta, joka sijaitsee halutun 25 katkaisukohdan ulkopuolella, poistetaan. Menetelmän periaate ilmenee seuraavasta kaaviosta, jossa "v" merkitsee haluttua katkaisukohtaa: a) ....... v_ haluttu katkaisukohta "v" 30 b) ...... y_ DNA tehdään yksi juosteiseksi "v":n molemmilta puolilta 25 c)...... v_ primeerin hybridisointi ***** * li 3 72344 d) .......v_ ketjua pidennetään primee- ristä alkaen e) .......v__ yksijuosteinen osa poistetaan
Edullisimmassa suoritusmudossa vaiheet (d) ja (e) suoritetaan samanaikaisesti käyttäen polymeraasia, 10 joka samanaikaisesti poistaa esiintyöntyvän yksijuostei- sen pään 3'—^5' -suunnassa ja pidentää primeeriä (dATPrn, dGTP:n, dTTPrn ja dCTP:n läsnäollessa) 5'—>3' -suunnassa. Tähän käytetään edullisesti Klenow-polymeraasia I (fragmentti, joka on valmistettu hajoittamalla proteolyyttises-15 ti DNA-polymeraasi I, joka sisältää alkuperäisen entsyymin polymerisoivan aktiivisuuden 5'—^3' -suunnassa sekä sen eksonukleolyyttisen aktiivisuuden 3'—>5' -suunnassa, mutta josta puuttuu alkuperäisen entsyymin eksonukleolyyt-tinen aktiivisuus 5'—»3' -suunnassa. Katso A. Kornberg, 20 DNA Synthesis 98, W.H. Freeman and Co., SFO (1974).
Edellä kuvatussa menetelmässä attenuaattoridelee-tiot voidaan tehdä millä tavalla tahansa trp-operonin sisältävässä plasmidissa, joka on ensin linearisoitu esimerkiksi katkaisemalla molekyyli restriktiokohdasta, joka 25 sijaitsee alavirtaan pisteestä, josta molekyyli on tarkoitus tehdä tylppäpäiseksi ("v" edellä mainitussa tapauksessa) . Kun heikentäjäalue on poistettu, molekyyli voidaan syklisoida uudelleen esimerkiksi liittämällä tylpät päät yhteen tai muilla asiantuntijalle itsestään selvillä ta-30 voilla.
Seuraava esimerkki havainnollistaa keksinnön mukaisen menetelmän suoritusta käytännössä.
Esimerkki:
Liitteenä olevaan kuvioon viitaten plasmidi pSom7 Δ 2 35 (katso FI-patenttihakemukset 810876 ja 853488) käsiteltiin Hind ΙΙΙ-restriktioentsyymillä ja sen jälkeen lambda-ekso-nukleaasilla (5’-3’-eksonukleaasi) sellaisissa olosuhteissa, 4 72344 joissa plasmidi saatiin hajoitetuksi Bgl II-restriktiokoh-dan yli, joka sijaitsi LE'-sekvenssiä koodaavalla alueella. 20 ng Hind 111:11a hajoitettua pSom7 Δ 2 -plasmidia ‘ -3
liuotettiin puskuriin (20 x 10 -m glysiinipuskuri, pH
-3 -3 5 9,6, joka sisälsi 1 x 10 -m MgC^ ja 1 x 10 -m yS-merkap- toetanolia). Muodostunut seos käsiteltiin 5 yksiköllä lambda-eksonukleaasia 60 minuutin ajan huoneen lämpötilassa. Näin saatu reaktioseos uutettiin fenolilla ja kloroformilla, ja DNA saostettiin etanolilla.
10 Jotta EcoRI-jäännös saataisiin muodostetuksi LE'- geenifragmentin distaaliseen päähän, syntetisoitiin 32 pCCTGTGCATGAT-primeeri parannetulla fosfotriesterime-netelmällä (R. Crea et ai., Proc. Nat'l Acad. Sei. USA 75 (1978) 576) ja se hybridisoitiin LE'-geenifragmentin 15 yksijuosteiseen päähän, joka oli muodostunut käsiteltäes sä plasmidia lambda-eksonukleaasilla. Hybridisointi suoritettiin seuraavaksi kuvatulla tavalla.
20 yug Hind ΙΙΙ-restriktioentsyymillä ja labda-eksonukleaasilla käsiteltyä pSom7 A 2 -plasmidituotetta 20 liuotettiin 20 yal:aan vettä, ja näin saatu liuos yhdistettiin 6 jul:aan liuosta, joka sisälsi noin 80 pikomoolia edellä kuvattua 5'-fosforyloitua oligonukleotidia. Synteettinen fragmentti hybridisoitiin LE'-koodaussekvenssin 3'-päähän, ja LE'-fragmentin jäljelle jäänyt yksijuosteinen 25 osa täytettiin käyttäen Klenow-polymeraasia I, dATP:n, dTTP:n, dGTP:n ja dCTP:n läsnäollessa.
Reaktioseos kuumennettiin 50°C:seen, minkä jälkeen sen annettiin jäähtyä hitaasti 10°C:seen, ja sen jälkeen lisättiin 4 jul Klenow-entsyymiä. Seosta inkuboitiin 15 mi-30 nuuttia huoneen lämpötilassa ja sen jälkeen 30 minuuttia 37°C:ssa, minkä jälkeen reaktio pysäytettiin lisäämällä 5 μΐ 0,25-m EDTA. Reaktioseos uutettiin fenolilla ja kloroformilla, ja DNA saostettiin etanolilla. Sen jälkeen DNA käsiteltiin resktriktioentsyymillä Bgl II. Muodostu-35 neet fragmentit fraktioitiin PAGE:11a. Geelin autoradio- grammi osoitti, että oli muodostunut halutun pituinen noin 32 5 72344 470 emäsparia sisältävä P-merkitty fragmentti, joka erotettiin elektroeluoimalla. Odotetusti tämän fragmentin (LE'(d)) Bgl II-pää ja tylppä pää osuivat primeerin alkukohtaan.
5 Keksinnön mukaista menetelmää voidaan käyttää esim.
FI-patenttihakemuksissa 810876 ja 853488 kuvatulla tavalla ekspressiovektorin muodostamiseen, joka sisältää Le'(d)-fragmentin (29) (katso kuvio) promoottorin (trp-promootto-ri-operaattorin) säätelyn alaisena, johon vektoriin voidaan 10 funktionaalisesti insertoida heterologista polypeptidiä, kuten tymosiini-alfa-1:tä, ihmisen insuliinin esiastetta tai ihmisen insuliinin A- tai B-ketjua koodaava sekvenssi. Muodostunut ekspressiovektori voidaan sitten transformoida sopivaan isäntäorganismiin (E. coli 294) heterolo-15 gisen polypeptidin ekspressoimiseksi.
Claims (3)
1. Menetelmä kaksijuosteisen DNA:n pilkkomiseksi mistä tahansa halutusta kohdasta, tunnettu siitä, 5 että menetelmään kuuluu seuraavat vaiheet: a) muutetaan kaksijuosteinen DNA yksijuosteiseksi katkaisukohdan molemmilta puolilta; b) hybridisoidaan vaiheessa (a) muodostuneeseen yksijuosteiseen alueeseen yksijuosteisen DNA:n komplemen- 10 taarinen primeeri, jonka 5'-pää sijaitsee vastapäätä halutun katkaisukohdan viereistä nukleotidia; c) muodostetaan uudelleen se osa toisesta juos-teesta, joka on poistettu vaiheessa (a) ja joka sijaitsee 3'-suunnassa mainittuun primeeriin nähden, antamalla vai- 15 heesta (b) saadun tuotteen reagoida DNA-polymeraasin kanssa adeniinia, tymiiniä, guaniinia ja sytosiinia sisältävien deoksinukleotiditrifosfaattien läsnäollessa; ja d) lohkaistaan irti jäljelle jäänyt yksijuosteinen DNA-fragmentti, joka työntyy esiin halutusta katkaisukoh- 20 dasta.
2. Patenttivaatimuksen 1 mukainen menetelmä, tunnettu siitä, että vaiheet (c) ja (d) suoritetaan samanaikaisesti antamalla vaiheessa (b) muodostuneen tuotteen reagoida DNA-polymeraasin kanssa, joka polymeri- 25 soi suunnassa 5' —> 3', on eksonukleolyyttinen suunnassa 3'—> 5', mutta ei-eksonukleolyyttinen suunnassa 5'—> 3’.
3. Patenttivaatimuksen 2 mukainen menetelmä, tunnettu siitä, että polymeraasina käytetään Klenow-polymeraasia I.
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US13329680A | 1980-03-24 | 1980-03-24 | |
US13329680 | 1980-03-24 | ||
FI810876A FI810876L (fi) | 1980-03-24 | 1981-03-20 | Expression av polypeptider i bakterier genom promotor/operatorn av tryptofangenen |
FI810876 | 1981-03-20 |
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FI853489L FI853489L (fi) | 1985-09-12 |
FI853489A0 FI853489A0 (fi) | 1985-09-12 |
FI72344B true FI72344B (fi) | 1987-01-30 |
FI72344C FI72344C (fi) | 1987-05-11 |
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FI810876A FI810876L (fi) | 1980-03-24 | 1981-03-20 | Expression av polypeptider i bakterier genom promotor/operatorn av tryptofangenen |
FI853488A FI853488A0 (fi) | 1980-03-24 | 1985-09-12 | Foerfarande foer framstaellning av en expressionsplasmid. |
FI853489A FI72344C (fi) | 1980-03-24 | 1985-09-12 | Foerfarande foer spjaelkning av dubbelstraengat dna. |
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FI810876A FI810876L (fi) | 1980-03-24 | 1981-03-20 | Expression av polypeptider i bakterier genom promotor/operatorn av tryptofangenen |
FI853488A FI853488A0 (fi) | 1980-03-24 | 1985-09-12 | Foerfarande foer framstaellning av en expressionsplasmid. |
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