CN113846102A - 一种rna编辑系统及其编辑方法与应用 - Google Patents
一种rna编辑系统及其编辑方法与应用 Download PDFInfo
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- CN113846102A CN113846102A CN202111225358.0A CN202111225358A CN113846102A CN 113846102 A CN113846102 A CN 113846102A CN 202111225358 A CN202111225358 A CN 202111225358A CN 113846102 A CN113846102 A CN 113846102A
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Abstract
本发明公开了一种RNA编辑系统及其编辑方法与应用，通过基因工程方法使重组RNA编辑酶连接上RNA结合结构域，当含有RNA结合结构域特异识别特征的外源RNA结合到RNA上时，重组RNA编辑酶活性会对靶标RNA进行切割或碱基修饰等操作。本发明方法实现了特异高效地对核酸分子RNA的编辑，可用于体内抑制基因表达、清除RNA病毒以及改变RNA序列，简单实用。
Description
技术领域
本发明属于基因工程技术领域，具体涉及一种RNA编辑系统及其编辑方法与应用。
背景技术
对目标RNA进行编辑具有很大的应用前景：
首先，在探索基因功能中的应用：后基因组时代阐明基因组中功能基因表达产物的生物学作用对医学发展有着深远意义。RNA编辑技术可以快速、经济、简便的以序列特异方式对目的基因表达调控以及对其表达产物进行一个修改，已经成为探索基因功能的重要研究手段。对阐明信号转导通路、发现新的药物作用靶点有重要意义。
其次，RNA编辑技术在基因治疗领域中的应用：RNA降解技术作为一种高效的序列特异性基因剔除技术在传染性疾病和恶性肿瘤基因治疗领域发展极为迅速。在利用RNAi技术对HIV-1、乙型肝炎、丙型肝炎等进行基因治疗研究中发现，选择病毒基因组中与人类基因组无同源性的序列作为抑制序列可在抑制病毒复制的同时避免对正常组织的毒副作用。同时将抑制序列选择在特定的位点，可对部分有明确基因突变的恶性肿瘤细胞如含有BCL/ABL或AML1/MTG8融合基因的白血病细胞产生凋亡诱导作用。此外尚可通过使用肿瘤特异性启动子如hTERT启动子、survivin启动子或组织特异性启动子如酪氨酸酶启动子、骨钙素启动子引导针对某些癌基因或抗凋亡分子的表达或产物进行编辑，从而达到特异性杀伤肿瘤细胞的目的。
最后，病毒性疾病的治疗：加州大学洛杉矶分校和加州理工学院的研究人员开发出使用RNAi技术来阻止艾滋病病毒进入人体细胞。这些结果提示RNA降解技术能胜任许多病毒的基因治疗，RNA降解技术将成为一种有效的抗病毒治疗手段。这对于许多严重的动物传染病的防治具有十分重大的意义。
目前对RNA编辑有基于Cas13或dCas13为基础的RNA编辑技术，这些技术的效率比较高，但是由于它们的分子量比较大，而且脱靶及旁切效果比较严重，制约了其在基因治疗中的应用。
发明内容
针对上述技术问题，本发明提供一种RNA编辑系统及其编辑方法与应用，能有效解决上述现有技术不足之处。
为解决现有技术问题，本发明采取的技术方案为：
一种RNA编辑系统，包括重组RNA编辑酶和指引RNA，且所述重组RNA编辑酶包括两个蛋白结构域，一个是与RNA结合的蛋白结构域，另一个是对RNA进行编辑的酶；所述指引RNA包括两段序列，一段是识别序列，所述识别序列与重组RNA编辑酶的RNA结合的蛋白结构域，另一段是反义序列，所述反义序列通过碱基互补配对原则与靶标RNA结合，从而实现对靶标RNA的编辑。
优选的，所述与RNA结合的蛋白结构域为PP7cp或HIV1 RNA转运蛋白Rev，其中，
PP7cp的氨基酸序列如SEQ ID NO.1所示，具体如下：
KTIVLSVGEATRTLTEIQSTADRQIFEEKVGPLVGRLRLTASLRQNGAKTAYRVNLKLDQADVVDCSTSVCGELPKVRYTQVWSHDVTIVANSTEASRKSLYDLTKSLVATSQVEDLVVNLVPLGR
HIV1 RNA转运蛋白Rev的氨基酸序列如 SEQ ID NO.2所示，具体如下：
MAGRSGDSDEELIRTVRLIKLLYQSNPPPNPEGTRQARRNRRRRWRERQRQIHSISERILGTYLGRSAEPVPLQLPPLERLTLDCNEDCGTSGTQGVGSPQILVESPTVLESGTKE
优选的，所述对RNA进行编辑的酶为降解RNA的RNA酶或对RNA进行碱基修饰的酶类。
进一步优选的是，所述对RNA进行编辑的酶包括具有双链特异的RNA酶、MCPIP1蛋白的RNA酶活性结构域、催化RNA碱基C转为碱基U的酶和催化RNA碱基A转为碱基I的酶，所述具有双链特异的RNA酶的氨基酸序列如SEQ ID NO.3所示，所述MCPIP1蛋白的RNA酶活性结构域的氨基酸序列如SEQ ID NO.4所示，所述催化RNA碱基C转为碱基U的酶的氨基酸序列如SEQ ID NO.5所示，所述催化RNA碱基A转为碱基I的酶的氨基酸序列如SEQ ID NO.6所示，其中，
具有双链特异的RNA酶的氨基酸序列如SEQ ID NO.3所示，具体如下：
NPIVINRLQRKLGYTFNHQELLQQALTHRSASSKHNERLEFLGDSILSYVIANALYHRFPRVDEGDMSRMRATLVRGNTLAELAREFELGECLRLGPGELKSGGFRRESILADTVEALIGGVFLDSDIQTVEKLILNWYQTRLDEISPGDKQKDPKTR
MCPIP1蛋白的RNA酶活性结构域的氨基酸序列如SEQ ID NO.4所示，具体如下：
TPKAPNLEPPLPEEEKEGSDLRPVVIDGSNVAMSHGNKEVFSCRGILLAVNWFLERGHTDITVFVPSWRKEQPRPDVPITDQHILRELEKKKILVFTPSRRVGGKRVVCYDDRFIVKLAYESDGIVVSNDTYRDLQGERQEWKRFIEERLLMYSFVNDKFMPPDDPLGRHGPSLDNFLRKKPLTLEHRKQPCPYGRKCTYGIKCRFFHPERPSCPQRSVA
催化RNA碱基C转为碱基U的酶的氨基酸序列如SEQ ID NO.5所示，具体如下：
RRAFITGVFYLSEVEFSHEYWMRHALTLAKRAWDEREVPVGAVLVHNNRVIGEGWNRPIGRHDPTAHAEIMALRQGGLVMQNYRLIDATLYVTLEPCVMCAGAMIHSRIGRVVFGARDAKTGAAGSLMDVLHHPGMNHRVEITEGILADECAALLSDFFRMRRQEIKAQKKAQSSTD
催化RNA碱基A转为碱基I的酶的氨基酸序列如SEQ ID NO.6所示，具体如下：
MSSETGPVAVDPTLRRRIEPHEFEVFFDPRELRKETCLLYEINWGGRHSIWRHTSQNTNKHVEVNFIEKFTTERYFCPNTRCSITWFLSWSPCGECSRAITEFLSRYPHVTLFIYIARLYHHADPRNRQGLRDLISSGVTIQIMTEQESGYCWRNFVNYSPSNEAHWPRYPHLWVRLYVLELYCIILGLPPCLNILRRKQPQLTFFTIALQSCHYQRLPPHILWATGLK
优选的，所述重组RNA编辑酶还包括核定位序列，其氨基酸序列如SEQ ID NO.7所示：PKKKRKV。
优选的，所述重组RNA编辑酶还包括柔性肽，其氨基酸序列如SEQ ID NO.8所示，所述柔性肽位于所述重组RNA编辑酶的两个蛋白结构域之间，其中， 柔性肽的氨基酸序列如SEQ ID NO.8所示：GGGGSGGGGSGGGG。
优选的，所述重组RNA编辑酶的C末端加入组蛋白纯化标签，N末端加入穿膜肽序列，所述组蛋白氨基酸序列如SEQ ID NO.9所示： CGRLWMRWYSPWARRYGC
上述RNA编辑系统的编辑方法，即应用上述的RNA编辑系统，将相应功能的酶引导到相应的RNA上，实现RNA的编辑。
上述RNA编辑系统或RNA编辑系统的编辑方法在敲降RNA、RNA碱基修改或RNA病毒清除中的应用。
有益效果：本发明所选择的RNA结合蛋白分子量较小，而且研究比较成熟，大大降低重组蛋白的分子量，适用于基因功能研究及RNA病毒清除等应用；另外，用于降解靶标RNA的编辑酶是一个双链特异性的RNA酶，使得它对单链RNA无作用，极大地减少旁切效果；该方法按照流行的分子生物学方法进行，所需要的试剂和仪器均为常用，无需特殊购买。
具体实施方式
下面通过具体实施例对本发明作详细说明：
实施例1
一种RNA编辑系统，用于敲降293T细胞中AMPKα亚基的mRNA水平，具体过程如下：
1）对RNA进行编辑的酶选为靶向切割RNA的酶，具体为RNC-PP7cp序列，将RNC-PP7cp序列构建到真核表达载体上，在同一载体把SEQ ID NO.11序列构建在U6或H1启动子后面，表达出指引RNA；
通过密码子优化后且于靶向降解RNA的RNC-PP7cp的DNA序列如SEQ ID NO.10所示，具体如下：
ATGCCCAAGAAGAAGCGCAAGGTGAACCCCATCGTGATCAACCGCCTGCAGCGCAAGCTGGGCTACACCTTCAACCACCAGGAGCTGCTGCAGCAGGCCCTGACCCACCGCAGCGCCAGCAGCAAGCACAACGAGCGCCTGGAGTTCCTGGGCGACAGCATCCTGAGCTACGTGATCGCCAACGCCCTGTACCACCGCTTCCCCCGCGTGGACGAGGGCGACATGAGCCGCATGCGCGCCACCCTGGTGCGCGGCAACACCCTGGCCGAGCTGGCCCGCGAGTTCGAGCTGGGCGAGTGCCTGCGCCTGGGCCCCGGCGAGCTGAAGAGCGGCGGCTTCCGCCGCGAGAGCATCCTGGCCGACACCGTGGAGGCCCTGATCGGCGGCGTGTTCCTGGACAGCGACATCCAGACCGTGGAGAAGCTGATCCTGAACTGGTACCAGACCCGCCTGGACGAGATCAGCCCCGGCGACAAGCAGAAGGACCCCAAGACCCGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAAGACCATCGTGCTGAGCGTGGGCGAGGCCACCCGCACCCTGACCGAGATCCAGAGCACCGCCGACCGCCAGATCTTCGAGGAGAAGGTGGGCCCCCTGGTGGGCCGCCTGCGCCTGACCGCCAGCCTGCGCCAGAACGGCGCCAAGACCGCCTACCGCGTGAACCTGAAGCTGGACCAGGCCGACGTGGTGGACTGCAGCACCAGCGTGTGCGGCGAGCTGCCCAAGGTGCGCTACACCCAGGTGTGGAGCCACGACGTGACCATCGTGGCCAACAGCACCGAGGCCAGCCGCAAGAGCCTGTACGACCTGACCAAGAGCCTGGTGGCCACCAGCCAGGTGGAGGACCTGGTGGTGAACCTGGTGCCCCTGGGCCGC
SEQ ID NO.11序列如下所示：
TAAGGAGTTTATATGGAAACCCTTAGAATTCAAATTCACCATCTGACATCATGTGGATCCTAAGGAGTT TATATGGAAACCCTTA
注：加粗标注的序列为与靶序列通过反向互补原则结合的序列；两端以下划线标注序列为RNC-PP7cp蛋白结合区。
2）把步骤1）所构建的重组载体转染至293T细胞中；
3）再次培养24-48小时，即可抑制AMPKα亚基表达。
实施例2
一种RNA编辑系统，用于对293T细胞中AMPKα亚基进行碱基C和碱基A进行编辑，具体过程如下：
1）把Rev-Tad-APOBEC1的DNA序列构建到真核表达载体上，使其表达靶向RNA的编辑酶，在同一载体把SEQ ID NO.13序列构建在U6或H1启动子后面，表达出指引RNA；
Rev-Tad-APOBEC1的DNA序列如SEQ ID NO.12所示，具体如下：
ATGCCCAAGAAGAAGCGCAAGGTGGCCGGCCGCAGCGGCGACAGCGACGAGGAGCTGATCCGCACCGTGCGCCTGATCAAGCTGCTGTACCAGAGCAACCCCCCCCCCAACCCCGAGGGCACCCGCCAGGCCCGCCGCAACCGCCGCCGCCGCTGGCGCGAGCGCCAGCGCCAGATCCACAGCATCAGCGAGCGCATCCTGGGCACCTACCTGGGCCGCAGCGCCGAGCCCGTGCCCCTGCAGCTGCCCCCCCTGGAGCGCCTGACCCTGGACTGCAACGAGGACTGCGGCACCAGCGGCACCCAGGGCGTGGGCAGCCCCCAGATCCTGGTGGAGAGCCCCACCGTGCTGGAGAGCGGCACCAAGGAGGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCCGCCGCGCCTTCATCACCGGCGTGTTCTACCTGAGCGAGGTGGAGTTCAGCCACGAGTACTGGATGCGCCACGCCCTGACCCTGGCCAAGCGCGCCTGGGACGAGCGCGAGGTGCCCGTGGGCGCCGTGCTGGTGCACAACAACCGCGTGATCGGCGAGGGCTGGAACCGCCCCATCGGCCGCCACGACCCCACCGCCCACGCCGAGATCATGGCCCTGCGCCAGGGCGGCCTGGTGATGCAGAACTACCGCCTGATCGACGCCACCCTGTACGTGACCCTGGAGCCCTGCGTGATGTGCGCCGGCGCCATGATCCACAGCCGCATCGGCCGCGTGGTGTTCGGCGCCCGCGACGCCAAGACCGGCGCCGCCGGCAGCCTGATGGACGTGCTGCACCACCCCGGCATGAACCACCGCGTGGAGATCACCGAGGGCATCCTGGCCGACGAGTGCGCCGCCCTGCTGAGCGACTTCTTCCGCATGCGCCGCCAGGAGATCAAGGCCCAGAAGAAGGCCCAGAGCAGCACCGACGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCATGAGCAGCGAGACCGGCCCCGTGGCCGTGGACCCCACCCTGCGCCGCCGCATCGAGCCCCACGAGTTCGAGGTGTTCTTCGACCCCCGCGAGCTGCGCAAGGAGACCTGCCTGCTGTACGAGATCAACTGGGGCGGCCGCCACAGCATCTGGCGCCACACCAGCCAGAACACCAACAAGCACGTGGAGGTGAACTTCATCGAGAAGTTCACCACCGAGCGCTACTTCTGCCCCAACACCCGCTGCAGCATCACCTGGTTCCTGAGCTGGAGCCCCTGCGGCGAGTGCAGCCGCGCCATCACCGAGTTCCTGAGCCGCTACCCCCACGTGACCCTGTTCATCTACATCGCCCGCCTGTACCACCACGCCGACCCCCGCAACCGCCAGGGCCTGCGCGACCTGATCAGCAGCGGCGTGACCATCCAGATCATGACCGAGCAGGAGAGCGGCTACTGCTGGCGCAACTTCGTGAACTACAGCCCCAGCAACGAGGCCCACTGGCCCCGCTACCCCCACCTGTGGGTGCGCCTGTACGTGCTGGAGCTGTACTGCATCATCCTGGGCCTGCCCCCCTGCCTGAACATCCTGCGCCGCAAGCAGCCCCAGCTGACCTTCTTCACCATCGCCCTGCAGAGCTGCCACTACCAGCGCCTGCCCCCCCACATCCTGTGGGCCACCGGCCTGAAG
SEQ ID NO.13序列如下所示：
AGGAGCTTTGTTCCTTGGGTTCTTGGGAGCAGCAGGAAGCACTATGGGCGCAGCCTCAATGACGCTGAC GGTACAGGCCAGACAATTATTGTCTGGTATAGTGCAGCAGCAGAACAATTTGCTGAGGGCTATTGAGGCGCAACAGC ATCTGTTGCAACTCACAGTCTGGGGCATCAAGCAGCTCCAGGCAAGAATCCTGGCTGTGGAAAGATACCTAAAGGAT CAACAGCTCCAAATTCACCATCTGACATCATGT
注：加粗标注的序列为与靶序列通过反向互补原则结合的序列；下划线标注序列为Rev蛋白结合区。
2）把步骤1）所构建的重组载体转染至293T细胞中；
3）再次培养24-48小时，即可使AMPKα亚基发生碱基改变。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
序列表
<110> 徐州医科大学
<120> 一种RNA编辑系统及其编辑方法与应用
<160> 13
<170> SIPOSequenceListing 1.0
<210> 1
<211> 126
<212> PRT
<213> bacterium PP7
<400> 1
Lys Thr Ile Val Leu Ser Val Gly Glu Ala Thr Arg Thr Leu Thr Glu
1 5 10 15
Ile Gln Ser Thr Ala Asp Arg Gln Ile Phe Glu Glu Lys Val Gly Pro
20 25 30
Leu Val Gly Arg Leu Arg Leu Thr Ala Ser Leu Arg Gln Asn Gly Ala
35 40 45
Lys Thr Ala Tyr Arg Val Asn Leu Lys Leu Asp Gln Ala Asp Val Val
50 55 60
Asp Cys Ser Thr Ser Val Cys Gly Glu Leu Pro Lys Val Arg Tyr Thr
65 70 75 80
Gln Val Trp Ser His Asp Val Thr Ile Val Ala Asn Ser Thr Glu Ala
85 90 95
Ser Arg Lys Ser Leu Tyr Asp Leu Thr Lys Ser Leu Val Ala Thr Ser
100 105 110
Gln Val Glu Asp Leu Val Val Asn Leu Val Pro Leu Gly Arg
115 120 125
<210> 2
<211> 116
<212> PRT
<213> HIV1 RNA转运蛋白(Human immunodeficiency virus)
<400> 2
Met Ala Gly Arg Ser Gly Asp Ser Asp Glu Glu Leu Ile Arg Thr Val
1 5 10 15
Arg Leu Ile Lys Leu Leu Tyr Gln Ser Asn Pro Pro Pro Asn Pro Glu
20 25 30
Gly Thr Arg Gln Ala Arg Arg Asn Arg Arg Arg Arg Trp Arg Glu Arg
35 40 45
Gln Arg Gln Ile His Ser Ile Ser Glu Arg Ile Leu Gly Thr Tyr Leu
50 55 60
Gly Arg Ser Ala Glu Pro Val Pro Leu Gln Leu Pro Pro Leu Glu Arg
65 70 75 80
Leu Thr Leu Asp Cys Asn Glu Asp Cys Gly Thr Ser Gly Thr Gln Gly
85 90 95
Val Gly Ser Pro Gln Ile Leu Val Glu Ser Pro Thr Val Leu Glu Ser
100 105 110
Gly Thr Lys Glu
115
<210> 3
<211> 158
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Asn Pro Ile Val Ile Asn Arg Leu Gln Arg Lys Leu Gly Tyr Thr Phe
1 5 10 15
Asn His Gln Glu Leu Leu Gln Gln Ala Leu Thr His Arg Ser Ala Ser
20 25 30
Ser Lys His Asn Glu Arg Leu Glu Phe Leu Gly Asp Ser Ile Leu Ser
35 40 45
Tyr Val Ile Ala Asn Ala Leu Tyr His Arg Phe Pro Arg Val Asp Glu
50 55 60
Gly Asp Met Ser Arg Met Arg Ala Thr Leu Val Arg Gly Asn Thr Leu
65 70 75 80
Ala Glu Leu Ala Arg Glu Phe Glu Leu Gly Glu Cys Leu Arg Leu Gly
85 90 95
Pro Gly Glu Leu Lys Ser Gly Gly Phe Arg Arg Glu Ser Ile Leu Ala
100 105 110
Asp Thr Val Glu Ala Leu Ile Gly Gly Val Phe Leu Asp Ser Asp Ile
115 120 125
Gln Thr Val Glu Lys Leu Ile Leu Asn Trp Tyr Gln Thr Arg Leu Asp
130 135 140
Glu Ile Ser Pro Gly Asp Lys Gln Lys Asp Pro Lys Thr Arg
145 150 155
<210> 4
<211> 220
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Thr Pro Lys Ala Pro Asn Leu Glu Pro Pro Leu Pro Glu Glu Glu Lys
1 5 10 15
Glu Gly Ser Asp Leu Arg Pro Val Val Ile Asp Gly Ser Asn Val Ala
20 25 30
Met Ser His Gly Asn Lys Glu Val Phe Ser Cys Arg Gly Ile Leu Leu
35 40 45
Ala Val Asn Trp Phe Leu Glu Arg Gly His Thr Asp Ile Thr Val Phe
50 55 60
Val Pro Ser Trp Arg Lys Glu Gln Pro Arg Pro Asp Val Pro Ile Thr
65 70 75 80
Asp Gln His Ile Leu Arg Glu Leu Glu Lys Lys Lys Ile Leu Val Phe
85 90 95
Thr Pro Ser Arg Arg Val Gly Gly Lys Arg Val Val Cys Tyr Asp Asp
100 105 110
Arg Phe Ile Val Lys Leu Ala Tyr Glu Ser Asp Gly Ile Val Val Ser
115 120 125
Asn Asp Thr Tyr Arg Asp Leu Gln Gly Glu Arg Gln Glu Trp Lys Arg
130 135 140
Phe Ile Glu Glu Arg Leu Leu Met Tyr Ser Phe Val Asn Asp Lys Phe
145 150 155 160
Met Pro Pro Asp Asp Pro Leu Gly Arg His Gly Pro Ser Leu Asp Asn
165 170 175
Phe Leu Arg Lys Lys Pro Leu Thr Leu Glu His Arg Lys Gln Pro Cys
180 185 190
Pro Tyr Gly Arg Lys Cys Thr Tyr Gly Ile Lys Cys Arg Phe Phe His
195 200 205
Pro Glu Arg Pro Ser Cys Pro Gln Arg Ser Val Ala
210 215 220
<210> 5
<211> 177
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Arg Arg Ala Phe Ile Thr Gly Val Phe Tyr Leu Ser Glu Val Glu Phe
1 5 10 15
Ser His Glu Tyr Trp Met Arg His Ala Leu Thr Leu Ala Lys Arg Ala
20 25 30
Trp Asp Glu Arg Glu Val Pro Val Gly Ala Val Leu Val His Asn Asn
35 40 45
Arg Val Ile Gly Glu Gly Trp Asn Arg Pro Ile Gly Arg His Asp Pro
50 55 60
Thr Ala His Ala Glu Ile Met Ala Leu Arg Gln Gly Gly Leu Val Met
65 70 75 80
Gln Asn Tyr Arg Leu Ile Asp Ala Thr Leu Tyr Val Thr Leu Glu Pro
85 90 95
Cys Val Met Cys Ala Gly Ala Met Ile His Ser Arg Ile Gly Arg Val
100 105 110
Val Phe Gly Ala Arg Asp Ala Lys Thr Gly Ala Ala Gly Ser Leu Met
115 120 125
Asp Val Leu His His Pro Gly Met Asn His Arg Val Glu Ile Thr Glu
130 135 140
Gly Ile Leu Ala Asp Glu Cys Ala Ala Leu Leu Ser Asp Phe Phe Arg
145 150 155 160
Met Arg Arg Gln Glu Ile Lys Ala Gln Lys Lys Ala Gln Ser Ser Thr
165 170 175
Asp
<210> 6
<211> 229
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Met Ser Ser Glu Thr Gly Pro Val Ala Val Asp Pro Thr Leu Arg Arg
1 5 10 15
Arg Ile Glu Pro His Glu Phe Glu Val Phe Phe Asp Pro Arg Glu Leu
20 25 30
Arg Lys Glu Thr Cys Leu Leu Tyr Glu Ile Asn Trp Gly Gly Arg His
35 40 45
Ser Ile Trp Arg His Thr Ser Gln Asn Thr Asn Lys His Val Glu Val
50 55 60
Asn Phe Ile Glu Lys Phe Thr Thr Glu Arg Tyr Phe Cys Pro Asn Thr
65 70 75 80
Arg Cys Ser Ile Thr Trp Phe Leu Ser Trp Ser Pro Cys Gly Glu Cys
85 90 95
Ser Arg Ala Ile Thr Glu Phe Leu Ser Arg Tyr Pro His Val Thr Leu
100 105 110
Phe Ile Tyr Ile Ala Arg Leu Tyr His His Ala Asp Pro Arg Asn Arg
115 120 125
Gln Gly Leu Arg Asp Leu Ile Ser Ser Gly Val Thr Ile Gln Ile Met
130 135 140
Thr Glu Gln Glu Ser Gly Tyr Cys Trp Arg Asn Phe Val Asn Tyr Ser
145 150 155 160
Pro Ser Asn Glu Ala His Trp Pro Arg Tyr Pro His Leu Trp Val Arg
165 170 175
Leu Tyr Val Leu Glu Leu Tyr Cys Ile Ile Leu Gly Leu Pro Pro Cys
180 185 190
Leu Asn Ile Leu Arg Arg Lys Gln Pro Gln Leu Thr Phe Phe Thr Ile
195 200 205
Ala Leu Gln Ser Cys His Tyr Gln Arg Leu Pro Pro His Ile Leu Trp
210 215 220
Ala Thr Gly Leu Lys
225
<210> 7
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Pro Lys Lys Lys Arg Lys Val
1 5
<210> 8
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
1 5 10
<210> 9
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Cys Gly Arg Leu Trp Met Arg Trp Tyr Ser Pro Trp Ala Arg Arg Tyr
1 5 10 15
Gly Cys
<210> 10
<211> 918
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
atgcccaaga agaagcgcaa ggtgaacccc atcgtgatca accgcctgca gcgcaagctg 60
ggctacacct tcaaccacca ggagctgctg cagcaggccc tgacccaccg cagcgccagc 120
agcaagcaca acgagcgcct ggagttcctg ggcgacagca tcctgagcta cgtgatcgcc 180
aacgccctgt accaccgctt cccccgcgtg gacgagggcg acatgagccg catgcgcgcc 240
accctggtgc gcggcaacac cctggccgag ctggcccgcg agttcgagct gggcgagtgc 300
ctgcgcctgg gccccggcga gctgaagagc ggcggcttcc gccgcgagag catcctggcc 360
gacaccgtgg aggccctgat cggcggcgtg ttcctggaca gcgacatcca gaccgtggag 420
aagctgatcc tgaactggta ccagacccgc ctggacgaga tcagccccgg cgacaagcag 480
aaggacccca agacccgcgg cggcggcggc agcggcggcg gcggcagcgg cggcggcggc 540
aagaccatcg tgctgagcgt gggcgaggcc acccgcaccc tgaccgagat ccagagcacc 600
gccgaccgcc agatcttcga ggagaaggtg ggccccctgg tgggccgcct gcgcctgacc 660
gccagcctgc gccagaacgg cgccaagacc gcctaccgcg tgaacctgaa gctggaccag 720
gccgacgtgg tggactgcag caccagcgtg tgcggcgagc tgcccaaggt gcgctacacc 780
caggtgtgga gccacgacgt gaccatcgtg gccaacagca ccgaggccag ccgcaagagc 840
ctgtacgacc tgaccaagag cctggtggcc accagccagg tggaggacct ggtggtgaac 900
ctggtgcccc tgggccgc 918
<210> 11
<211> 85
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 11
taaggagttt atatggaaac ccttagaatt caaattcacc atctgacatc atgtggatcc 60
taaggagttt atatggaaac cctta 85
<210> 12
<211> 1671
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 12
atgcccaaga agaagcgcaa ggtggccggc cgcagcggcg acagcgacga ggagctgatc 60
cgcaccgtgc gcctgatcaa gctgctgtac cagagcaacc ccccccccaa ccccgagggc 120
acccgccagg cccgccgcaa ccgccgccgc cgctggcgcg agcgccagcg ccagatccac 180
agcatcagcg agcgcatcct gggcacctac ctgggccgca gcgccgagcc cgtgcccctg 240
cagctgcccc ccctggagcg cctgaccctg gactgcaacg aggactgcgg caccagcggc 300
acccagggcg tgggcagccc ccagatcctg gtggagagcc ccaccgtgct ggagagcggc 360
accaaggagg gcggcggcgg cagcggcggc ggcggcagcg gcggcggcgg ccgccgcgcc 420
ttcatcaccg gcgtgttcta cctgagcgag gtggagttca gccacgagta ctggatgcgc 480
cacgccctga ccctggccaa gcgcgcctgg gacgagcgcg aggtgcccgt gggcgccgtg 540
ctggtgcaca acaaccgcgt gatcggcgag ggctggaacc gccccatcgg ccgccacgac 600
cccaccgccc acgccgagat catggccctg cgccagggcg gcctggtgat gcagaactac 660
cgcctgatcg acgccaccct gtacgtgacc ctggagccct gcgtgatgtg cgccggcgcc 720
atgatccaca gccgcatcgg ccgcgtggtg ttcggcgccc gcgacgccaa gaccggcgcc 780
gccggcagcc tgatggacgt gctgcaccac cccggcatga accaccgcgt ggagatcacc 840
gagggcatcc tggccgacga gtgcgccgcc ctgctgagcg acttcttccg catgcgccgc 900
caggagatca aggcccagaa gaaggcccag agcagcaccg acggcggcgg cggcagcggc 960
ggcggcggca gcggcggcgg cggcatgagc agcgagaccg gccccgtggc cgtggacccc 1020
accctgcgcc gccgcatcga gccccacgag ttcgaggtgt tcttcgaccc ccgcgagctg 1080
cgcaaggaga cctgcctgct gtacgagatc aactggggcg gccgccacag catctggcgc 1140
cacaccagcc agaacaccaa caagcacgtg gaggtgaact tcatcgagaa gttcaccacc 1200
gagcgctact tctgccccaa cacccgctgc agcatcacct ggttcctgag ctggagcccc 1260
tgcggcgagt gcagccgcgc catcaccgag ttcctgagcc gctaccccca cgtgaccctg 1320
ttcatctaca tcgcccgcct gtaccaccac gccgaccccc gcaaccgcca gggcctgcgc 1380
gacctgatca gcagcggcgt gaccatccag atcatgaccg agcaggagag cggctactgc 1440
tggcgcaact tcgtgaacta cagccccagc aacgaggccc actggccccg ctacccccac 1500
ctgtgggtgc gcctgtacgt gctggagctg tactgcatca tcctgggcct gcccccctgc 1560
ctgaacatcc tgcgccgcaa gcagccccag ctgaccttct tcaccatcgc cctgcagagc 1620
tgccactacc agcgcctgcc cccccacatc ctgtgggcca ccggcctgaa g 1671
<210> 13
<211> 256
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 13
aggagctttg ttccttgggt tcttgggagc agcaggaagc actatgggcg cagcctcaat 60
gacgctgacg gtacaggcca gacaattatt gtctggtata gtgcagcagc agaacaattt 120
gctgagggct attgaggcgc aacagcatct gttgcaactc acagtctggg gcatcaagca 180
gctccaggca agaatcctgg ctgtggaaag atacctaaag gatcaacagc tccaaattca 240
ccatctgaca tcatgt 256
Claims (9)
1.一种RNA编辑系统，其特征在于：包括重组RNA编辑酶和指引RNA，且所述重组RNA编辑酶包括两个蛋白结构域，一个是与RNA结合的蛋白结构域，另一个是对RNA进行编辑的酶；所述指引RNA包括两段序列，一段是识别序列，所述识别序列与重组RNA编辑酶的RNA结合的蛋白结构域结合，另一段是反义序列，所述反义序列通过碱基互补配对原则与靶标RNA结合，从而实现对靶标RNA的编辑。
2.根据权利要求1所述的一种RNA编辑系统，其特征在于：所述与RNA结合的蛋白结构域为PP7cp或HIV1 RNA转运蛋白Rev，所述PP7cp的氨基酸序列如SEQ ID NO.1所示，所述HIV1RNA转运蛋白Rev的氨基酸序列如 SEQ ID NO.2所示。
3.根据权利要求1所述的一种RNA编辑系统，其特征在于：所述对RNA进行编辑的酶为降解RNA的RNA酶或对RNA进行碱基修饰的酶类。
4.根据权利要求3所述的一种RNA编辑的系统，其特征在于：所述对RNA进行编辑的酶包括具有双链特异的RNA酶、MCPIP1蛋白的RNA酶活性结构域、催化RNA碱基C转为碱基U的酶和催化RNA碱基A转为碱基I的酶，所述具有双链特异的RNA酶的氨基酸序列如SEQ ID NO.3所示，所述MCPIP1蛋白的RNA酶活性结构域的氨基酸序列如SEQ ID NO.4所示，所述催化RNA碱基C转为碱基U的酶的氨基酸序列如SEQ ID NO.5所示，所述催化RNA碱基A转为碱基I的酶的氨基酸序列如SEQ ID NO.6所示。
5.根据权利要求1所述的一种RNA编辑系统，其特征在于：所述重组RNA编辑酶还包括核定位序列，其氨基酸序列如SEQ ID NO.7所示。
6.根据权利要求1所述的一种RNA编辑系统，其特征在于：所述重组RNA编辑酶还包括柔性肽，其氨基酸序列如SEQ ID NO.8所示，所述柔性肽位于所述重组RNA编辑酶的两个蛋白结构域之间。
7.根据权利要求1所述的一种RNA编辑系统，其特征在于：所述重组RNA编辑酶的C末端加入组蛋白纯化标签，N末端加入穿膜肽序列，所述组蛋白氨基酸序列如SEQ ID NO.9所示。
8.基于权利要求1所述的一种RNA编辑系统的编辑方法，其特征在于：应用权利要求1-7任一项所述的RNA编辑系统，将相应功能的酶引导到相应的RNA上，实现RNA的编辑。
9.基于权利要求1所述的RNA编辑系统或权利要求8所述的编辑方法在敲降RNA、RNA碱基修改或RNA病毒清除中的应用。
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| CN110520163A (zh) * | 2017-01-05 | 2019-11-29 | 新泽西鲁特格斯州立大学 | 独立于dna双链断裂的靶向基因编辑平台及其用途 |
| CN111629786A (zh) * | 2017-10-06 | 2020-09-04 | 俄勒冈健康与科学大学 | 用于编辑rna的组合物和方法 |
| US20200392473A1 (en) * | 2017-12-22 | 2020-12-17 | The Broad Institute, Inc. | Novel crispr enzymes and systems |
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| CN110520163A (zh) * | 2017-01-05 | 2019-11-29 | 新泽西鲁特格斯州立大学 | 独立于dna双链断裂的靶向基因编辑平台及其用途 |
| CN111629786A (zh) * | 2017-10-06 | 2020-09-04 | 俄勒冈健康与科学大学 | 用于编辑rna的组合物和方法 |
| US20200392473A1 (en) * | 2017-12-22 | 2020-12-17 | The Broad Institute, Inc. | Novel crispr enzymes and systems |
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