N~6-甲基腺苷相关蛋白及其对非编码RNA调控的研究进展
|
摘要
N~6-甲基腺苷(m~6A)是指发生在腺嘌呤第6位氮原子上的甲基化修饰,广泛存在于多种真核生物的RNA中。当前研究显示m~6A相关蛋白主要包括催化m~6A形成的甲基转移酶、移除m~6A修饰的去甲基化酶和识别m~6A修饰的甲基结合蛋白三类。近年研究发现微小RNA(miRNA)、长链非编码RNA(lncRNA)和环状RNA(circRNA)等非编码RNA的生成和功能发挥受到m~6A修饰的调控。本文基于近期的文献,总结了m~6A相关蛋白的种类和功能的研究进展,并对m~6A相关蛋白调控非编码RNA生成和功能发挥的机制进行归纳,以期为将来m~6A相关蛋白及其对非编码RNA的影响研究提供参考。
N~6-methyladenosine(m~6A), abundant in eukaryotic RNAs, refers to methylation of the adenosine base at the nitrogen-6 position. m~6 A has been recognized to be regulated by three categories of proteins, of which methyltransferases catalyze the formation of m~6 A modification, demethylases erase m~6A markers from RNA, and methyl-binding proteins selectively recognize m~6 A modification. In recent years, increasing research has revealed that m~6 A plays an important role in production and functioning of non-coding RNAs such as microRNA(miRNA), long non-coding RNA(lncRNA), and circular RNA(circRNA). According to the latest reports, this paper summarized the types and functions of m~6A-related proteins, as well as the mechanisms of m~6 A regulatory proteins on the production and functioning of non-coding RNAs, aiming to provide reference for future research on m~6A-related proteins and their effects on non-coding RNAs.
N~6-methyladenosine(m~6A), abundant in eukaryotic RNAs, refers to methylation of the adenosine base at the nitrogen-6 position. m~6 A has been recognized to be regulated by three categories of proteins, of which methyltransferases catalyze the formation of m~6 A modification, demethylases erase m~6A markers from RNA, and methyl-binding proteins selectively recognize m~6 A modification. In recent years, increasing research has revealed that m~6 A plays an important role in production and functioning of non-coding RNAs such as microRNA(miRNA), long non-coding RNA(lncRNA), and circular RNA(circRNA). According to the latest reports, this paper summarized the types and functions of m~6A-related proteins, as well as the mechanisms of m~6 A regulatory proteins on the production and functioning of non-coding RNAs, aiming to provide reference for future research on m~6A-related proteins and their effects on non-coding RNAs.
引文
[1]DESROSIERS R,FRIDERICI K,ROTTMAN F.Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells[J].Proc Natl Acad Sci USA,1974,77(9):3971-3975.
[2]DOMINISSINI D,MOSHITCH-MOSHKOVITZ S,SCHWARTZ S,et al.Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq[J].Nature,2012,485(7397):201-206.
[3]MEYER K D,SALETORE Y,ZUMBO P,et al.Comprehensive analysis of mRNA methylation reveals enrichment in 3'UTRs and near stop codons[J].Cell,2012,149(7):1635-1646.
[4]BERULAVA T,RAHMANN S,RADEMACHER K,et al.N6-adenosine methylation in miRNAs[J].PLoS One,2015,10(2):e0118438.
[5]WARDA A S,KRETSCHMER J,HACKERT P,et al.Human METTL16 is a N6-methyladenosine(m6A)methyltransferase that targets pre-mRNAs and various non-coding RNAs[J].EMBO Rep,2017,18(11):2004-2014.
[6]JACOB R,ZANDER S,GUTSCHNER T.The dark side of the epitranscriptome:chemical modifications in long noncoding RNAs[J].Int J Mol Sci,2017,18(11):2387.
[7]PATIL D P,CHEN C K,PICKERING B F,et al.m6A RNAmethylation promotes XIST-mediated transcriptional repression[J].Nature,537(7620):369-373.
[8]YANG Y,FAN X,MAO M,et al.Extensive translation of circular RNAs driven by N6-methyladenosine[J].Cell Res,2017,27(5):626-641.
[9]DAI D,WANG H,ZHU L,et al.N6-methyladenosine links RNA metabolism to cancer progression[J].Cell Death Dis,2018,9(2):124.
[10]MEYER K D,JAFFREY S R.Rethinking m6A readers,writers,and erasers[J].Annu Rev Cell Dev Biol,2017,33:319-342.
[11]BOKAR J A,RATH-SHAMBAUGH M E,LUDWICZAK R,et al.Characterization and partial purification of mRNA N6-adenosine methyltransferase from HeLa cell nuclei.Internal mRNA methylation requires a multisubunit complex[J].JBiol Chem,1994,269(26):17697-17704.
[12]LIU J,YUE Y,HAN D,et al.A METTL3-METTL14 complex m e d i a t e s m a m m a l i a n n u c l e a r R N A N6-a d e n o s i n e methylation[J].Nat Chem Biol,2014,10(2):93-95.
[13]PING X L,SUN B F,WANG L,et al.Mammalian WTAPis a regulatory subunit of the RNA N6-methyladenosine methyltransferase[J].Cell Res,2014,24(2):177-189.
[14]SCHWARTZ S,MUMBACH M R,JOVANOVIC M,et al.Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5'sites[J].Cell Rep,2014,8(1):284-296.
[15]YUE Y,LIU J,CUI X,et al.VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation[J].Cell Discov,2018,4:10.
[16]WEN J,LV R,MA H,et al.Zc3h13 regulates nuclear RNAm6A methylation and mouse embryonic stem cell selfrenewal[J].Mol Cell,2018,69(6):1028-1038.e6.
[17]JIA G,FU Y,ZHAO X,et al.N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated[J].Nat Chem Biol,2011,7(12):885-887.
[18]ZHENG G,DAHL JA,NIU Y,et al.ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility[J].Mol Cell,2013,49(1):18-29.
[19]YI C,YANG C G,HE C.A non-heme Iron-mediated chemical demethylation in DNA and RNA[J].Acc Chem Res,2009,42(4):519-529.
[20]WANG X,ZHAO B S,ROUNDTREE I A,et al.N6-methyladenosine modulates messenger RNA translation efficiency[J].Cell,2015,161(6):1388-1399.
[21]HSU P J,ZHU Y,MA H,et al.Ythdc2 is an N6-methyladenosine binding protein that regulates mammalian spermatogenesis[J].Cell Res,2017,27(9):1115-1127.
[22]WANG X,LU Z,GOMEZ A,et al.N6-methyladenosinedependent regulation of messenger RNA stability[J].Nature,2014,505(481):117-120.
[23]SHI H,WANG X,LU Z,et al.YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA[J].Cell Res,2017,27(3):315-328.
[24]XIAO W,ADHIKARI S,DAHAL U,et al.Nuclear m6A reader YTHDC1 regulates mRNA splicing[J].Mol Cell,2016,61(4):507-519.
[25]ROUNDTREE I A,LUO G Z,ZHANG Z,et al.YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs[J].eLife,2017,6:e31311.
[26]ALARCóN C R,GOODARZI H,LEE H,et al.HNRNPA2B1 is a mediator of m6A-dependent nuclear RNA processing events[J].Cell,2015,162(2):1299-1308.
[27]MEYER K D,PATIL D P,ZHOU J,et al.5'UTR m6A promotes cap-independent translation[J].Cell,2015,163(4):999-1010.
[28]HUANG H,WENG H,SUN W,et al.Recognition of RNAN6-methyladenosine by IGF2BP proteins enhances mRNAstability and translation[J].Nat Cell Biol,2018,20(3):285-295.
[29]ZHOU K I,PARISIEN M,DAI Q,et al.N6-Methyladenosine modification in a long noncoding RNA hairpin predisposes its conformation to protein binding[J].J Mol Biol,2016,428:822-833.
[30]LIU N,DAI Q,ZHENG G,et al.N6-methyladenosinedependent RNA structural switches regulate RNA-protein interactions[J].Nature,2015,518(7540):560-564.
[31]LIU N,ZHOU K I,PARISIEN M,et al.N6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein[J].Nucleic Acids Res,2017,45(10):6051-6063.
[32]WEI W,JI X,GUO X,et al.Regulatory role of N6-methyladenosine(m6A)methylation in RNA processing and human diseases[J].J Cell Biochem,2017,118(9):2534-2543.
[33]PARK J H,SHIN C.MicroRNA-directed cleavage of targets:mechanism and experimental approaches[J].BMB Rep,2014,47(8):417-423.
[34]OLENA A F,PATTON J G.Genomic organization of microRNAs[J].J Cell Physiol,2010,222(3):540-545.
[35]ALARCóN C R,LEE H,GOODARZI H,et al.N6-methyladenosine marks primary microRNAs for processing[J].Nature,2015,519(7544):482-485.
[36]MA J Z,YANG F,ZHOU C C,et al.METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N6-methyladenosine-dependent primary MicroRNA processing[J].Hepatology,2017,65(2):529-543.
[37]GU S,SUN D,DAI H,et al.N6-methyladenosine mediates the cellular proliferation and apoptosis via microRNAs in arsenite-transformed cells[J].Toxicol Lett,2018,292:1-11.
[38]CHEN T,HAO Y J,ZHANG Y,et al.m6A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency[J].Cell Stem Cell,2015,16(3):289-301.
[39]DU M,ZHANG Y,MAO Y,et al.MiR-33a suppresses proliferation of NSCLC cells via targeting METTL3 mRNA[J].Biochem Biophys Res Commun,2017,482(4):582-589.
[40]CAI X,WANG X,CAO C,et al.HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g[J].Cancer Lett,2018,415:11-19.
[41]YANG Z,LI J,FENG G,et al.MicroRNA-145 modulates N6-methyladenosine levels by targeting the 3'-untranslated mRNA region of the N6-methyladenosine binding YTHdomain family 2 protein[J].J Biol Chem,2017,292(9):3614-3623.
[42]周凤燕,杨青,朱熙春,等.环状RNA的分子特征、作用机制及生物学功能[J].农业生物技术学报,2017,25(3):485-501.
[43]韩泽平,何金花,黎毓光.长链非编码RNA与糖尿病关系的研究进展[J].中国病理生理杂志,2014,30(4):751-756.
[44]SONG J,YE A,JIANG E,et al.Reconstruction and analysis of the aberrant lncRNA-miRNA-mRNA network based on competitive endogenous RNA in CESC[J].J Cell Biochem,2018,119(8):6665-6673.
[45]PANG K C,STEPHEN S,ENGSTR?M P G,et al.RNAdb-a comprehensive mammalian noncoding RNA database[J].Nucleic Acids Res,2005,33(Database issue):D125-D130.
[46]LIU N,PARISIEN M,DAI Q,et al.Probing N6-methyladenosine RNA modification status at single nucleotide resolution in mRNA and long noncoding RNA[J].RNA,2013,19(12):1848-1856.
[47]YANG D,QIAO J,WANG G,et al.N6-methyladenosine modification of lincRNA 1281 is critically required for mESCdifferentiation potential[J].Nucleic Acids Res,2018,46(8):3906-3920.
[2]DOMINISSINI D,MOSHITCH-MOSHKOVITZ S,SCHWARTZ S,et al.Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq[J].Nature,2012,485(7397):201-206.
[3]MEYER K D,SALETORE Y,ZUMBO P,et al.Comprehensive analysis of mRNA methylation reveals enrichment in 3'UTRs and near stop codons[J].Cell,2012,149(7):1635-1646.
[4]BERULAVA T,RAHMANN S,RADEMACHER K,et al.N6-adenosine methylation in miRNAs[J].PLoS One,2015,10(2):e0118438.
[5]WARDA A S,KRETSCHMER J,HACKERT P,et al.Human METTL16 is a N6-methyladenosine(m6A)methyltransferase that targets pre-mRNAs and various non-coding RNAs[J].EMBO Rep,2017,18(11):2004-2014.
[6]JACOB R,ZANDER S,GUTSCHNER T.The dark side of the epitranscriptome:chemical modifications in long noncoding RNAs[J].Int J Mol Sci,2017,18(11):2387.
[7]PATIL D P,CHEN C K,PICKERING B F,et al.m6A RNAmethylation promotes XIST-mediated transcriptional repression[J].Nature,537(7620):369-373.
[8]YANG Y,FAN X,MAO M,et al.Extensive translation of circular RNAs driven by N6-methyladenosine[J].Cell Res,2017,27(5):626-641.
[9]DAI D,WANG H,ZHU L,et al.N6-methyladenosine links RNA metabolism to cancer progression[J].Cell Death Dis,2018,9(2):124.
[10]MEYER K D,JAFFREY S R.Rethinking m6A readers,writers,and erasers[J].Annu Rev Cell Dev Biol,2017,33:319-342.
[11]BOKAR J A,RATH-SHAMBAUGH M E,LUDWICZAK R,et al.Characterization and partial purification of mRNA N6-adenosine methyltransferase from HeLa cell nuclei.Internal mRNA methylation requires a multisubunit complex[J].JBiol Chem,1994,269(26):17697-17704.
[12]LIU J,YUE Y,HAN D,et al.A METTL3-METTL14 complex m e d i a t e s m a m m a l i a n n u c l e a r R N A N6-a d e n o s i n e methylation[J].Nat Chem Biol,2014,10(2):93-95.
[13]PING X L,SUN B F,WANG L,et al.Mammalian WTAPis a regulatory subunit of the RNA N6-methyladenosine methyltransferase[J].Cell Res,2014,24(2):177-189.
[14]SCHWARTZ S,MUMBACH M R,JOVANOVIC M,et al.Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5'sites[J].Cell Rep,2014,8(1):284-296.
[15]YUE Y,LIU J,CUI X,et al.VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation[J].Cell Discov,2018,4:10.
[16]WEN J,LV R,MA H,et al.Zc3h13 regulates nuclear RNAm6A methylation and mouse embryonic stem cell selfrenewal[J].Mol Cell,2018,69(6):1028-1038.e6.
[17]JIA G,FU Y,ZHAO X,et al.N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated[J].Nat Chem Biol,2011,7(12):885-887.
[18]ZHENG G,DAHL JA,NIU Y,et al.ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility[J].Mol Cell,2013,49(1):18-29.
[19]YI C,YANG C G,HE C.A non-heme Iron-mediated chemical demethylation in DNA and RNA[J].Acc Chem Res,2009,42(4):519-529.
[20]WANG X,ZHAO B S,ROUNDTREE I A,et al.N6-methyladenosine modulates messenger RNA translation efficiency[J].Cell,2015,161(6):1388-1399.
[21]HSU P J,ZHU Y,MA H,et al.Ythdc2 is an N6-methyladenosine binding protein that regulates mammalian spermatogenesis[J].Cell Res,2017,27(9):1115-1127.
[22]WANG X,LU Z,GOMEZ A,et al.N6-methyladenosinedependent regulation of messenger RNA stability[J].Nature,2014,505(481):117-120.
[23]SHI H,WANG X,LU Z,et al.YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA[J].Cell Res,2017,27(3):315-328.
[24]XIAO W,ADHIKARI S,DAHAL U,et al.Nuclear m6A reader YTHDC1 regulates mRNA splicing[J].Mol Cell,2016,61(4):507-519.
[25]ROUNDTREE I A,LUO G Z,ZHANG Z,et al.YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs[J].eLife,2017,6:e31311.
[26]ALARCóN C R,GOODARZI H,LEE H,et al.HNRNPA2B1 is a mediator of m6A-dependent nuclear RNA processing events[J].Cell,2015,162(2):1299-1308.
[27]MEYER K D,PATIL D P,ZHOU J,et al.5'UTR m6A promotes cap-independent translation[J].Cell,2015,163(4):999-1010.
[28]HUANG H,WENG H,SUN W,et al.Recognition of RNAN6-methyladenosine by IGF2BP proteins enhances mRNAstability and translation[J].Nat Cell Biol,2018,20(3):285-295.
[29]ZHOU K I,PARISIEN M,DAI Q,et al.N6-Methyladenosine modification in a long noncoding RNA hairpin predisposes its conformation to protein binding[J].J Mol Biol,2016,428:822-833.
[30]LIU N,DAI Q,ZHENG G,et al.N6-methyladenosinedependent RNA structural switches regulate RNA-protein interactions[J].Nature,2015,518(7540):560-564.
[31]LIU N,ZHOU K I,PARISIEN M,et al.N6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein[J].Nucleic Acids Res,2017,45(10):6051-6063.
[32]WEI W,JI X,GUO X,et al.Regulatory role of N6-methyladenosine(m6A)methylation in RNA processing and human diseases[J].J Cell Biochem,2017,118(9):2534-2543.
[33]PARK J H,SHIN C.MicroRNA-directed cleavage of targets:mechanism and experimental approaches[J].BMB Rep,2014,47(8):417-423.
[34]OLENA A F,PATTON J G.Genomic organization of microRNAs[J].J Cell Physiol,2010,222(3):540-545.
[35]ALARCóN C R,LEE H,GOODARZI H,et al.N6-methyladenosine marks primary microRNAs for processing[J].Nature,2015,519(7544):482-485.
[36]MA J Z,YANG F,ZHOU C C,et al.METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N6-methyladenosine-dependent primary MicroRNA processing[J].Hepatology,2017,65(2):529-543.
[37]GU S,SUN D,DAI H,et al.N6-methyladenosine mediates the cellular proliferation and apoptosis via microRNAs in arsenite-transformed cells[J].Toxicol Lett,2018,292:1-11.
[38]CHEN T,HAO Y J,ZHANG Y,et al.m6A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency[J].Cell Stem Cell,2015,16(3):289-301.
[39]DU M,ZHANG Y,MAO Y,et al.MiR-33a suppresses proliferation of NSCLC cells via targeting METTL3 mRNA[J].Biochem Biophys Res Commun,2017,482(4):582-589.
[40]CAI X,WANG X,CAO C,et al.HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g[J].Cancer Lett,2018,415:11-19.
[41]YANG Z,LI J,FENG G,et al.MicroRNA-145 modulates N6-methyladenosine levels by targeting the 3'-untranslated mRNA region of the N6-methyladenosine binding YTHdomain family 2 protein[J].J Biol Chem,2017,292(9):3614-3623.
[42]周凤燕,杨青,朱熙春,等.环状RNA的分子特征、作用机制及生物学功能[J].农业生物技术学报,2017,25(3):485-501.
[43]韩泽平,何金花,黎毓光.长链非编码RNA与糖尿病关系的研究进展[J].中国病理生理杂志,2014,30(4):751-756.
[44]SONG J,YE A,JIANG E,et al.Reconstruction and analysis of the aberrant lncRNA-miRNA-mRNA network based on competitive endogenous RNA in CESC[J].J Cell Biochem,2018,119(8):6665-6673.
[45]PANG K C,STEPHEN S,ENGSTR?M P G,et al.RNAdb-a comprehensive mammalian noncoding RNA database[J].Nucleic Acids Res,2005,33(Database issue):D125-D130.
[46]LIU N,PARISIEN M,DAI Q,et al.Probing N6-methyladenosine RNA modification status at single nucleotide resolution in mRNA and long noncoding RNA[J].RNA,2013,19(12):1848-1856.
[47]YANG D,QIAO J,WANG G,et al.N6-methyladenosine modification of lincRNA 1281 is critically required for mESCdifferentiation potential[J].Nucleic Acids Res,2018,46(8):3906-3920.