m~6A修饰及其对病毒复制过程调控研究进展
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摘要
N6-甲基腺嘌呤(N~6-methyladenosine, m~6A)修饰是一种在真核生物中普遍存在的RNA修饰方式,在mRNA转运、稳定、翻译等过程中具有重要作用。m~6A修饰在病毒复制周期中扮演不同的角色,病毒的复制和宿主对病毒的免疫反应都受到m~6A甲基化的影响。本文总结了近年来关于m6A修饰方面的分子作用机制及其对病毒复制以及宿主免疫反应的影响相关研究,以期为病毒生命周期中的表观遗传调控研究提供一定的参考。
N~6-methyladenosine(m~6A) is a prevalent modification of RNA in eukaryotes and plays an important role in the process of mRNA translocation, stabilization and translation. m~6A exerts different influences on the viral replication cycle, and both viral replication and host immune response to the virus are affected by m~6A. In this review,we summarize recent studies on the mechanism of m6A modification and its effects on viral replication and host immune response, in order to provide a reference for epigenetic regulation in the viral life cycle.
N~6-methyladenosine(m~6A) is a prevalent modification of RNA in eukaryotes and plays an important role in the process of mRNA translocation, stabilization and translation. m~6A exerts different influences on the viral replication cycle, and both viral replication and host immune response to the virus are affected by m~6A. In this review,we summarize recent studies on the mechanism of m6A modification and its effects on viral replication and host immune response, in order to provide a reference for epigenetic regulation in the viral life cycle.
引文
[1]Desrosiers R,Friderici K,Rottman F.Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells.Proc Natl Acad Sci USA,1974,71(10):3971-3975.
[2]Perry RP,Kelley DE.Existence of methylated messenger RNA in mouse L cells.Cell,1974,1(1):37-42.
[3]Ye F,Dan D,Gideon R,Chuan H.Gene expression regulation mediated through reversible m6A RNA methylation.Nat Rev Genet,2014,15(5):293-306.
[4]LI YL,YU J,Song SH.Recent progresses in RNAN6-methyladenosine research.Hereditas(Beijing),2013,35(12):1340-1351.李语丽,于军,宋述慧.RNA中6-甲基腺嘌呤的研究进展.遗传,2013,35(12):1340-1351.
[5]Zhao BS,Roundtree IA,He C.Post-transcriptional gene regulation by mRNA modifications.Nat Rev Mol Cell Biol,2016,18(1):31-42.
[6]Roignant JY,Soller M.M6A in mRNA:an ancient mechanism for Fine-Tuning gene expression.Trends in Genetics,2017,33(6):380-390.
[7]Wu R,Jiang D,Wang Y,Wang X.N6-methyladenosine(m6A)methylation in mRNA with a dynamic and reversible epigenetic modification.Mol Biotechnol,2016,58(7):450-459.
[8]Krug RM,Morgan MA,Shatkin AJ.Influenza viral mRNAcontains internal N6-methyladenosine and 5'-terminal7-methylguanosine in cap structures.J Virol,1976,20(1):45-53.
[9]Moss B,Koczot F.Sequence of methylated nucleotides at the 5'-terminus of adenovirus-specific RNA.J Virol,1976,17(2):385-392.
[10]Tan B,Gao SJ.RNA epitranscriptomics:regulation of infection of RNA and DNA viruses by N6-methyladenosine(m6A).Quaest Math,2018,29(1):125-131.
[11]Zhang X,Jia GF.RNA epigenetic modification:N6-methyladenosine.Hereditas(Beijing),2016,38(4):275-288.张笑,贾桂芳.RNA表观遗传修饰:N6-甲基腺嘌呤.遗传,2016,38(4):275-288.
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[13]Horiuchi K,Kawamura T,Iwanari H,Ohashi R,Naito M,Kodama T,Hamakubo T.Identification of Wilms'tumor1-associating protein complex and its role in alternative splicing and the cell cycle.J Biol Chem 2013,288(46):33292-33302.
[14]Pendleton KE,Chen B,Liu K,Hunter OV,Xie Y,Tu BP,Conrad NK.The U6 snRNA m6A methyltransferase METTL16 regulates SAM synthetase intron retention.Cell,2017,169(5):824-835.e14.
[15]Jia G,Fu Y,Zhao X,Dai Q,Zheng G,Yang Y,Yi C,Lindahl T,Pan T,Yang YG,He C.N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO.Nat Chem Biol,2011,7(12):885-887.
[16]Zheng G,Dahl JA,Niu Y,Fedorcsak P,Huang CM,Li CJ,V?gb?CB,Shi Y,Wang WL,Song SH,Lu Z,Bosmans RP,Dai Q,Hao YJ,Yang X,Zhao WM,Tong WM,Wang XJ,Bogdan F,Furu K,Fu Y,Jia G,Zhao X,Liu J,Krokan HE,Klungland A,Yang YG,He C.ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.Mol Cell,2012,49(1):18-29.
[17]Aik WS,Scotti JS,Choi H,Gong L,Demetriades M,Schofield CJ,Mcdonough MA.Structure of human RNAN6-methyladenine demethylase ALKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation.Nucleic Acids Res,2014,42(7):4741-4754.
[18]Mauer J,Luo X,Blanjoie A,Jiao X,Grozhik AV,Patil DP,Linder B,Pickering BF,Vasseur JJ,Chen Q,Gross SS,Elemento O,Debart F,Kiledjian M,Jaffrey SR.Reversible methylation of m6Am in the 5'cap controls mRNAstability.Nature,2016,541(7637):371-375.
[19]Patil DP,Pickering BF,Jaffrey SR.Reading m6A in the transcriptome:m6A-binding proteins.Trends Cell Biol,2017,28(2):113-127.
[20]Xiao W,Lu Z,Gomez A,Hon GC,Yue Y,Han D,Ye F,Parisien M,Dai Q,Jia G.m6A-dependent regulation of messenger RNA stability.Nature,2014,505(7481):117-120.
[21]Meyer KD,Jaffrey SR.Rethinking m(6)A Readers,Writers,and Erasers.Annu Rev Cell Dev Biol,2017,33(1):319-342.
[22]Patil DP,Chen CK,Pickering BF,Chow A,Jackson C,Guttman M,Jaffrey SR.m6A RNA methylation promotes XIST-mediated transcriptional repression.Nature,2016,537(7620):369-373.
[23]Wang X,Lu Z,Gomez A,Hon GC,Yue Y,Han D,Fu Y,Parisien M,Dai Q,Jia G,Ren B,Pan T,He C.N6-methyladenosine-dependent regulation of messenger RNA stability.Nature,2013,505(7481):117-120.
[24]Wang Y,Li Y,Toth JI,Petroski MD,Zhang Z,Zhao JC.N6-methyladenosine dification destabilizes developmental regulators in embryonic stem cells.Nat Cell Biol,2014,16(2):191-198.
[25]Du H,Zhao Y,He J,Zhang Y,Xi H,Liu M,Ma J,Wu L.YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex.Nat Commun,2016,7:12626.
[26]Zhou J,Wang J,Gao X,Zhang X,Jaffrey SR,Qian SB.Dynamic m(6)A mRNA methylation directs translational control of heat shock response.Nature,2015,526(7574):591-594.
[27]Xiao W,Adhikari S,Dahal U,Chen YS,Hao YJ,Sun BF,Sun HY,Li A,Ping XL,Lai WY,Wang X,Ma HL,Huang CM,Yang Y,Huang N,Jiang GB,Wang HL,Zhou Q,Wang XJ,Zhao YL,Yang YG.Nuclear m(6)A reader YTHDC1 regulates mRNA splicing.Mol Cell,2016,61(4):507-519.
[28]Ying Y,Chen YS,Sun BF,Yang YG.RNA methylation:regulations and mechanisms.Hereditas(Beijing),2018,40(11):964-976.杨莹,陈宇晟,孙宝发,杨运桂.RNA甲基化修饰调控和规律.遗传,2018,40(11):964-976.
[29]Duan HC,Wang Y,Jia G.Dynamic and reversible RNAN6-methyladenosine methylation.Wires Rna,2018,10(1):e1507.
[30]Lichinchi G,Gao S,Saletore Y,Gonzalez GM,Bansal V,Wang Y,Mason CE,Rana TM.Dynamics of the human and viral m(6)A RNA methylomes during HIV-1 infection of T cells.Nat Microbiol,2016,1(4):16011.
[31]Kennedy E,Bogerd H,Kornepati AR,Kang D,Ghoshal D,Marshall JB,Poling BC,Tsai K,Gokhale N,Horner SM.Posttranscriptional m6A editing of HIV-1 mRNAs enhances viral gene expression.Cell Host Microbe,2017,22(6):830.
[32]Tirumuru N,Zhao BS,Lu W,Lu Z,He C,Wu L.Correction:N(6)-methyladenosine of HIV-1 RNA regulates viral infection and HIV-1 Gag protein expression.eLife,2016,5:e15528.
[33]Lu W,Tirumuru N,St Gelais C,Koneru PC,Liu C,Kvaratskhelia M,He C,Wu L.N6-methyladenosinebinding proteins suppress HIV-1 infectivity and viral production.J Biol Chem,2018,293(34):12992-13005.
[34]Narayan P,Ayers DF,Rottman FM,Maroney PA,Nilsen TW.Unequal distribution of N6-methyladenosine in influenza virus mRNAs.Mol Cell Biol,1987,7(4):1572-1575.
[35]Courtney DG,Kennedy EM,Dumm RE,Bogerd HP,Tsai K,Heaton NS,Cullen BR.Epitranscriptomic enhancement of influenza A virus gene expression and replication.Cell Host Microbe,2017,22(3):377-386.e5.
[36]Lichinchi G,Zhao BS,Wu Y,Lu Z,Qin Y,He C,Rana T.Dynamics of human and viral RNA methylation during Zika virus infection.Cell Host Microbe,2016,20(5):666-673.
[37]Gokhale N,Mcintyre ARR,Mcfadden M,Roder A,Kennedy E,Gandara J,Hopcraft S,Quicke K,Vazquez C,Willer J.N6-methyladenosine in flaviviridae viral RNAgenomes regulates infection.Cell Host Microbe,2016,20(5):654-665.
[38]Imam H,Khan M,Gokhale NS,McIntyre ABR,Kim G-W,Jang JY,Kim S-J,Mason CE,Horner SM,Siddiqui A.N6-methyladenosine modification of hepatitis B virus RNA differentially regulates the viral life cycle.Proc Natl Acad Sci USA,2018,115(35):8829-8834.
[39]Ye F,Lei X,Gao SJ.Mechanisms of Kaposi's SarcomaAssociated herpesvirus latency and reactivation.Adv Virol,2011,2011(1687-8639).
[40]Tan B,Hui L,Zhang S,Silva S RD,Lin Z,Jia M,Cui X,Yuan H,Sorel O,Zhang SW.Viral and cellular N 6-methyladenosine and N6,2′-O-dimethyladenosine epitranscriptomes in the KSHV life cycle.Nat Microbiol,2017,3(1):108-120.
[41]Hesser CR,Karijolich J,Dominissini D,He C,Glaunsinger BA.N6-methyladenosine modification and the YTHDF2 reader protein play cell type specific roles in lytic viral gene expression during Kaposi's sarcomaassociated herpesvirus infection.PLoS Pathog,2018,14(4):e1006995.
[42]Tsai K,Courtney DG,Cullen BR.Addition of m6A to SV40 late mRNAs enhances viral structural gene expression and replication.PLoS Pathog,2018,14(2):e1006919.
[43]Martínez-Pérez M,Aparicio F,López-Gresa MP,Bellés JM,Sánchez-Navarro JA,Pallás V.Arabidopsis m6Ademethylase activity modulates viral infection of a plant virus and the m6A abundance in its genomic RNAs.Proc Natl Acad Sci USA,2017,114(40):10755-10760.
[44]Durbin AF,Wang C,Marcotrigiano J,Gehrke L.RNAs containing modified nucleotides fail to trigger RIG-Iconformational changes for innate immune signaling.Mbio,2016,7(5):e00833-16.
[45]KarikóK,Buckstein M,NiH,Weissman D.Suppression of RNA recognition by Toll-like receptors:the Impact of nucleoside modification and the evolutionary origin of RNA.Immunity,2005,23(2):165-175.
[46]Kennedy EM,Courtney DG,Tsai K,Cullen BR.Viral Epitranscriptomics.J Virol,2017,91(9):JVI.02263-16.
[47]Bader JP,Brown NR,Chiang PK,Cantoni GL.3-Deazaadenosine,an inhibitor of adenosylhomocysteine hydrolase,inhibits reproduction of Rous sarcoma virus and transformation of chick embryo cells.Virology,1978,89(2):494-505.
[48]Chiang PK.Biological effects of inhibitors of S-adenosylhomocysteine hydrolase.Pharmacol Therapeut,1998,77(2):115-134.
[2]Perry RP,Kelley DE.Existence of methylated messenger RNA in mouse L cells.Cell,1974,1(1):37-42.
[3]Ye F,Dan D,Gideon R,Chuan H.Gene expression regulation mediated through reversible m6A RNA methylation.Nat Rev Genet,2014,15(5):293-306.
[4]LI YL,YU J,Song SH.Recent progresses in RNAN6-methyladenosine research.Hereditas(Beijing),2013,35(12):1340-1351.李语丽,于军,宋述慧.RNA中6-甲基腺嘌呤的研究进展.遗传,2013,35(12):1340-1351.
[5]Zhao BS,Roundtree IA,He C.Post-transcriptional gene regulation by mRNA modifications.Nat Rev Mol Cell Biol,2016,18(1):31-42.
[6]Roignant JY,Soller M.M6A in mRNA:an ancient mechanism for Fine-Tuning gene expression.Trends in Genetics,2017,33(6):380-390.
[7]Wu R,Jiang D,Wang Y,Wang X.N6-methyladenosine(m6A)methylation in mRNA with a dynamic and reversible epigenetic modification.Mol Biotechnol,2016,58(7):450-459.
[8]Krug RM,Morgan MA,Shatkin AJ.Influenza viral mRNAcontains internal N6-methyladenosine and 5'-terminal7-methylguanosine in cap structures.J Virol,1976,20(1):45-53.
[9]Moss B,Koczot F.Sequence of methylated nucleotides at the 5'-terminus of adenovirus-specific RNA.J Virol,1976,17(2):385-392.
[10]Tan B,Gao SJ.RNA epitranscriptomics:regulation of infection of RNA and DNA viruses by N6-methyladenosine(m6A).Quaest Math,2018,29(1):125-131.
[11]Zhang X,Jia GF.RNA epigenetic modification:N6-methyladenosine.Hereditas(Beijing),2016,38(4):275-288.张笑,贾桂芳.RNA表观遗传修饰:N6-甲基腺嘌呤.遗传,2016,38(4):275-288.
[12]Schwartz S,Mumbach MR,Jovanovic M,Wang T,Maciag K,Bushkin GG,Mertins P,Ter-ovanesyan D,Habib N,Cacchiarelli D,Sanjana NE,Freinkman E,Pacold ME,Satija R,Mikkelsen TS,Hacohen N,Zhang F,Carr SA,Lander ES,Regev A.Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and5'sites.Cell Rep,2014,8(1):284-296.
[13]Horiuchi K,Kawamura T,Iwanari H,Ohashi R,Naito M,Kodama T,Hamakubo T.Identification of Wilms'tumor1-associating protein complex and its role in alternative splicing and the cell cycle.J Biol Chem 2013,288(46):33292-33302.
[14]Pendleton KE,Chen B,Liu K,Hunter OV,Xie Y,Tu BP,Conrad NK.The U6 snRNA m6A methyltransferase METTL16 regulates SAM synthetase intron retention.Cell,2017,169(5):824-835.e14.
[15]Jia G,Fu Y,Zhao X,Dai Q,Zheng G,Yang Y,Yi C,Lindahl T,Pan T,Yang YG,He C.N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO.Nat Chem Biol,2011,7(12):885-887.
[16]Zheng G,Dahl JA,Niu Y,Fedorcsak P,Huang CM,Li CJ,V?gb?CB,Shi Y,Wang WL,Song SH,Lu Z,Bosmans RP,Dai Q,Hao YJ,Yang X,Zhao WM,Tong WM,Wang XJ,Bogdan F,Furu K,Fu Y,Jia G,Zhao X,Liu J,Krokan HE,Klungland A,Yang YG,He C.ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.Mol Cell,2012,49(1):18-29.
[17]Aik WS,Scotti JS,Choi H,Gong L,Demetriades M,Schofield CJ,Mcdonough MA.Structure of human RNAN6-methyladenine demethylase ALKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation.Nucleic Acids Res,2014,42(7):4741-4754.
[18]Mauer J,Luo X,Blanjoie A,Jiao X,Grozhik AV,Patil DP,Linder B,Pickering BF,Vasseur JJ,Chen Q,Gross SS,Elemento O,Debart F,Kiledjian M,Jaffrey SR.Reversible methylation of m6Am in the 5'cap controls mRNAstability.Nature,2016,541(7637):371-375.
[19]Patil DP,Pickering BF,Jaffrey SR.Reading m6A in the transcriptome:m6A-binding proteins.Trends Cell Biol,2017,28(2):113-127.
[20]Xiao W,Lu Z,Gomez A,Hon GC,Yue Y,Han D,Ye F,Parisien M,Dai Q,Jia G.m6A-dependent regulation of messenger RNA stability.Nature,2014,505(7481):117-120.
[21]Meyer KD,Jaffrey SR.Rethinking m(6)A Readers,Writers,and Erasers.Annu Rev Cell Dev Biol,2017,33(1):319-342.
[22]Patil DP,Chen CK,Pickering BF,Chow A,Jackson C,Guttman M,Jaffrey SR.m6A RNA methylation promotes XIST-mediated transcriptional repression.Nature,2016,537(7620):369-373.
[23]Wang X,Lu Z,Gomez A,Hon GC,Yue Y,Han D,Fu Y,Parisien M,Dai Q,Jia G,Ren B,Pan T,He C.N6-methyladenosine-dependent regulation of messenger RNA stability.Nature,2013,505(7481):117-120.
[24]Wang Y,Li Y,Toth JI,Petroski MD,Zhang Z,Zhao JC.N6-methyladenosine dification destabilizes developmental regulators in embryonic stem cells.Nat Cell Biol,2014,16(2):191-198.
[25]Du H,Zhao Y,He J,Zhang Y,Xi H,Liu M,Ma J,Wu L.YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex.Nat Commun,2016,7:12626.
[26]Zhou J,Wang J,Gao X,Zhang X,Jaffrey SR,Qian SB.Dynamic m(6)A mRNA methylation directs translational control of heat shock response.Nature,2015,526(7574):591-594.
[27]Xiao W,Adhikari S,Dahal U,Chen YS,Hao YJ,Sun BF,Sun HY,Li A,Ping XL,Lai WY,Wang X,Ma HL,Huang CM,Yang Y,Huang N,Jiang GB,Wang HL,Zhou Q,Wang XJ,Zhao YL,Yang YG.Nuclear m(6)A reader YTHDC1 regulates mRNA splicing.Mol Cell,2016,61(4):507-519.
[28]Ying Y,Chen YS,Sun BF,Yang YG.RNA methylation:regulations and mechanisms.Hereditas(Beijing),2018,40(11):964-976.杨莹,陈宇晟,孙宝发,杨运桂.RNA甲基化修饰调控和规律.遗传,2018,40(11):964-976.
[29]Duan HC,Wang Y,Jia G.Dynamic and reversible RNAN6-methyladenosine methylation.Wires Rna,2018,10(1):e1507.
[30]Lichinchi G,Gao S,Saletore Y,Gonzalez GM,Bansal V,Wang Y,Mason CE,Rana TM.Dynamics of the human and viral m(6)A RNA methylomes during HIV-1 infection of T cells.Nat Microbiol,2016,1(4):16011.
[31]Kennedy E,Bogerd H,Kornepati AR,Kang D,Ghoshal D,Marshall JB,Poling BC,Tsai K,Gokhale N,Horner SM.Posttranscriptional m6A editing of HIV-1 mRNAs enhances viral gene expression.Cell Host Microbe,2017,22(6):830.
[32]Tirumuru N,Zhao BS,Lu W,Lu Z,He C,Wu L.Correction:N(6)-methyladenosine of HIV-1 RNA regulates viral infection and HIV-1 Gag protein expression.eLife,2016,5:e15528.
[33]Lu W,Tirumuru N,St Gelais C,Koneru PC,Liu C,Kvaratskhelia M,He C,Wu L.N6-methyladenosinebinding proteins suppress HIV-1 infectivity and viral production.J Biol Chem,2018,293(34):12992-13005.
[34]Narayan P,Ayers DF,Rottman FM,Maroney PA,Nilsen TW.Unequal distribution of N6-methyladenosine in influenza virus mRNAs.Mol Cell Biol,1987,7(4):1572-1575.
[35]Courtney DG,Kennedy EM,Dumm RE,Bogerd HP,Tsai K,Heaton NS,Cullen BR.Epitranscriptomic enhancement of influenza A virus gene expression and replication.Cell Host Microbe,2017,22(3):377-386.e5.
[36]Lichinchi G,Zhao BS,Wu Y,Lu Z,Qin Y,He C,Rana T.Dynamics of human and viral RNA methylation during Zika virus infection.Cell Host Microbe,2016,20(5):666-673.
[37]Gokhale N,Mcintyre ARR,Mcfadden M,Roder A,Kennedy E,Gandara J,Hopcraft S,Quicke K,Vazquez C,Willer J.N6-methyladenosine in flaviviridae viral RNAgenomes regulates infection.Cell Host Microbe,2016,20(5):654-665.
[38]Imam H,Khan M,Gokhale NS,McIntyre ABR,Kim G-W,Jang JY,Kim S-J,Mason CE,Horner SM,Siddiqui A.N6-methyladenosine modification of hepatitis B virus RNA differentially regulates the viral life cycle.Proc Natl Acad Sci USA,2018,115(35):8829-8834.
[39]Ye F,Lei X,Gao SJ.Mechanisms of Kaposi's SarcomaAssociated herpesvirus latency and reactivation.Adv Virol,2011,2011(1687-8639).
[40]Tan B,Hui L,Zhang S,Silva S RD,Lin Z,Jia M,Cui X,Yuan H,Sorel O,Zhang SW.Viral and cellular N 6-methyladenosine and N6,2′-O-dimethyladenosine epitranscriptomes in the KSHV life cycle.Nat Microbiol,2017,3(1):108-120.
[41]Hesser CR,Karijolich J,Dominissini D,He C,Glaunsinger BA.N6-methyladenosine modification and the YTHDF2 reader protein play cell type specific roles in lytic viral gene expression during Kaposi's sarcomaassociated herpesvirus infection.PLoS Pathog,2018,14(4):e1006995.
[42]Tsai K,Courtney DG,Cullen BR.Addition of m6A to SV40 late mRNAs enhances viral structural gene expression and replication.PLoS Pathog,2018,14(2):e1006919.
[43]Martínez-Pérez M,Aparicio F,López-Gresa MP,Bellés JM,Sánchez-Navarro JA,Pallás V.Arabidopsis m6Ademethylase activity modulates viral infection of a plant virus and the m6A abundance in its genomic RNAs.Proc Natl Acad Sci USA,2017,114(40):10755-10760.
[44]Durbin AF,Wang C,Marcotrigiano J,Gehrke L.RNAs containing modified nucleotides fail to trigger RIG-Iconformational changes for innate immune signaling.Mbio,2016,7(5):e00833-16.
[45]KarikóK,Buckstein M,NiH,Weissman D.Suppression of RNA recognition by Toll-like receptors:the Impact of nucleoside modification and the evolutionary origin of RNA.Immunity,2005,23(2):165-175.
[46]Kennedy EM,Courtney DG,Tsai K,Cullen BR.Viral Epitranscriptomics.J Virol,2017,91(9):JVI.02263-16.
[47]Bader JP,Brown NR,Chiang PK,Cantoni GL.3-Deazaadenosine,an inhibitor of adenosylhomocysteine hydrolase,inhibits reproduction of Rous sarcoma virus and transformation of chick embryo cells.Virology,1978,89(2):494-505.
[48]Chiang PK.Biological effects of inhibitors of S-adenosylhomocysteine hydrolase.Pharmacol Therapeut,1998,77(2):115-134.