International Journal of Clinical Research

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International Journal of Clinical Research. 2021; 5: (3) ; 10.12208/j.ijcr.20210021 .

The action mechanism of eukaryotic 5-methylcytosine (M5C) RNA methyltransferase
真核5-甲基胞嘧啶 (m5C) RNA甲基转移酶的作用机制研究

作者: 栾娜, 周钦, 王建伟*,

浙江大学医学院第二附属医院教育部肿瘤预防与干预重点实验室结直肠外科 浙江杭州

*通讯作者: 王建伟,单位:浙江大学医学院第二附属医院教育部肿瘤预防与干预重点实验室结直肠外科 浙江杭州;

引用本文: 栾娜, 周钦, 王建伟, 真核5-甲基胞嘧啶 (m5C) RNA甲基转移酶的作用机制研究[J]. 国际临床研究杂志, 2021; 5: (3) : 4-10.
Published: 2021/8/27 17:28:12


5-甲基胞嘧啶(m5C)是一种丰富的核糖核酸(RNA)修饰,其存在于多种RNA中,包括细胞质和线粒体的核糖体RNA (rRNAs)和转移RNA (tRNAs),以及信使RNA (mRNA)、增强子RNA (eRNAs)和一些非编码RNA。在真核生物中,RNA胞嘧啶的C5甲基化是由NOL1/NOP2/SUN结构域(NSUN)家族的酶以及DNA甲基转移酶同源物DNMT2催化的。近年来,甲基转移酶催化的底物RNA和修饰的靶核苷酸已经得到鉴定,结构分析和生化分析学为研究这些酶是如何实现靶特异性奠定了基础。这些酶的功能特征及其介导的修饰揭示了它们在线粒体和核基因表达的不同方面的重要作用。重要的是,这些发现使我们能够更好地理解编码m5C甲基转移酶的基因突变或这些酶的表达水平的改变所导致的一些疾病的分子基础。

关键词: RNA甲基转移酶;RNA修饰;表观转录组;5-甲基胞嘧啶;转移RNA(tRNA);信使RNA(mRNA)


5-methylcytosine (m5C) is a rich ribonucleic acid (RNA) modification, which exists in a variety of RNA, including cytoplasmic and mitochondrial ribosomal RNA(RRNAs) and transfer RNA(tRNAs), as well as messenger RNA(mRNA), enhancer RNA(Ernas) and some non-coding RNAs. In eukaryotes, C5 methylation of RNA cytosine is catalyzed by enzymes in the NOL1/NOP2/SUN domain (NSUN) family and DNA methyltransferase homologous DNMT2. In recent years, substrate RNA and modified target nucleotides catalyzed by methyltransferases have been identified, and structural and biochemical analyses have laid the foundation for the study of how these enzymes achieve target specificity. The functional characteristics of these enzymes and their mediated modifications reveal their important roles in different aspects of mitochondrial and nuclear gene expression. Importantly, these findings enable us to better understand the molecular basis of some diseases caused by mutations in the genes that encode M5C methyltransferase or by changes in the expression levels of these enzymes.

Key words: RNA methyltransferase; RNA modification; Apparent transcriptome; 5-methylcytosine; Transfer RNA (tRNA); Messenger RNA (mRNA)

参考文献 References

[1] Boccaletto, P., et al., MODOMICS: a database of RNA modification pathways. 2017 update. Nucleic Acids Res, 2018. 46(D1): p. D303-D307.

[2] Breiling, A. and F. Lyko, Epigenetic regulatory functions of DNA modifications: 5-methylcytosine and beyond. Epigenetics Chromatin, 2015. 8: p. 24.

[3] Reid, R., P.J. Greene, and D.V. Santi, Exposition of a family of RNA m(5)C methyltransferases from searching genomic and proteomic sequences. Nucleic Acids Res, 1999. 27(15): p. 3138-45.

[4] Liu, Y. and D.V. Santi, m5C RNA and m5C DNA methyl transferases use different cysteine residues as catalysts. Proc Natl Acad Sci U S A, 2000. 97(15): p. 8263-5.

[5] King, M.Y. and K.L. Redman, RNA methyltransferases utilize two cysteine residues in the formation of 5-methylcytosine. Biochemistry, 2002. 41(37): p. 11218-25.

[6] King, M., D. Ton, and K.L. Redman, A conserved motif in the yeast nucleolar protein Nop2p contains an essential cysteine residue. Biochem J, 1999. 337 ( Pt 1): p. 29-35.

[7] Blanco, S., et al., Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders. EMBO J, 2014. 33(18): p. 2020-39.

[8] Xing, J., et al., NSun2 Promotes Cell Growth via Elevating Cyclin-Dependent Kinase 1 Translation. Mol Cell Biol, 2015. 35(23): p. 4043-52.

[9] Redman, K.L., Assembly of protein-RNA complexes using natural RNA and mutant forms of an RNA cytosine methyltransferase. Biomacromolecules, 2006. 7(12): p. 3321-6.

[10] Jeltsch, A., Beyond Watson and Crick: DNA methylation and molecular enzymology of DNA methyltransferases. Chembiochem, 2002. 3(4): p. 274-93.

[11] Cheng, X., Structure and function of DNA methyltransferases. Annu Rev Biophys Biomol Struct, 1995. 24: p. 293-318.

[12] Watkins, N.J. and M.T. Bohnsack, The box C/D and H/ACA snoRNPs: key players in the modification, processing and the dynamic folding of ribosomal RNA. Wiley Interdiscip Rev RNA, 2012. 3(3): p. 397-414.

[13] Sloan, K.E., et al., Tuning the ribosome: The influence of rRNA modification on eukaryotic ribosome biogenesis and function. RNA Biol, 2017. 14(9): p. 1138-1152.

[14] Schosserer, M., et al., Methylation of ribosomal RNA by NSUN5 is a conserved mechanism modulating organismal lifespan. Nat Commun, 2015. 6: p. 6158.

[15] Gigova, A., et al., A cluster of methylations in the domain IV of 25S rRNA is required for ribosome stability. RNA, 2014. 20(10): p. 1632-44.

[16] Hayrapetyan, A., H. Grosjean, and M. Helm, Effect of a quaternary pentamine on RNA stabilization and enzymatic methylation. Biol Chem, 2009. 390(9): p. 851-61.

[17] Motorin, Y. and M. Helm, tRNA stabilization by modified nucleotides. Biochemistry, 2010. 49(24): p. 4934-44.

[18] Sharma, S. and D.L.J. Lafontaine, 'View From A Bridge': A New Perspective on Eukaryotic rRNA Base Modification. Trends Biochem Sci, 2015. 40(10): p. 560-575.

[19] Sloan, K.E., M.T. Bohnsack, and N.J. Watkins, The 5S RNP couples p53 homeostasis to ribosome biogenesis and nucleolar stress. Cell Rep, 2013. 5(1): p. 237-47.

[20] Haag, S., J. Kretschmer, and M.T. Bohnsack, WBSCR22/Merm1 is required for late nuclear pre-ribosomal RNA processing and mediates N7-methylation of G1639 in human 18S rRNA. RNA, 2015. 21(2): p. 180-7.

[21] Brzezicha, B., et al., Identification of human tRNA:m5C methyltransferase catalysing intron-dependent m5C formation in the first position of the anticodon of the pre-tRNA Leu (CAA). Nucleic Acids Res, 2006. 34(20): p. 6034-43.

[22] Goll, M.G., et al., Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science, 2006. 311(5759): p. 395-8.

[23] Haag, S., et al., NSUN6 is a human RNA methyltransferase that catalyzes formation of m5C72 in specific tRNAs. RNA, 2015. 21(9): p. 1532-43.

[24] Chan, C.T., et al., Reprogramming of tRNA modifications controls the oxidative stress response by codon-biased translation of proteins. Nat Commun, 2012. 3: p. 937.

[25] Shanmugam, R., et al., Cytosine methylation of tRNA-Asp by DNMT2 has a role in translation of proteins containing poly-Asp sequences. Cell Discov, 2015. 1: p. 15010.

[26] Tuorto, F., et al., The tRNA methyltransferase Dnmt2 is required for accurate polypeptide synthesis during haematopoiesis. EMBO J, 2015. 34(18): p. 2350-62.

[27] Dudek, J., P. Rehling, and M. van der Laan, Mitochondrial protein import: common principles and physiological networks. Biochim Biophys Acta, 2013. 1833(2): p. 274-85.

[28] Haag, S., et al., NSUN3 and ABH1 modify the wobble position of mt-tRNAMet to expand codon recognition in mitochondrial translation. EMBO J, 2016. 35(19): p. 2104-2119.

[29] Metodiev, M.D., et al., NSUN4 is a dual function mitochondrial protein required for both methylation of 12S rRNA and coordination of mitoribosomal assembly. PLoS Genet, 2014. 10(2): p. e1004110.

[30] Camara, Y., et al., MTERF4 regulates translation by targeting the methyltransferase NSUN4 to the mammalian mitochondrial ribosome. Cell Metab, 2011. 13(5): p. 527-39.

[31] Sloan, K.E., C. Hobartner, and M.T. Bohnsack, How RNA modification allows non-conventional decoding in mitochondria. Cell Cycle, 2017. 16(2): p. 145-146.

[32] Squires, J.E., et al., Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA. Nucleic Acids Res, 2012. 40(11): p. 5023-33.

[33] Amort, T., et al., Distinct 5-methylcytosine profiles in poly(A) RNA from mouse embryonic stem cells and brain. Genome Biol, 2017. 18(1): p. 1.

[34] Edelheit, S., et al., Transcriptome-wide mapping of 5-methylcytidine RNA modifications in bacteria, archaea, and yeast reveals m5C within archaeal mRNAs. PLoS Genet, 2013. 9(6): p. e1003602.

[35] Yang, X., et al., 5-methylcytosine promotes mRNA export - NSUN2 as the methyltransferase and ALYREF as an m(5)C reader. Cell Res, 2017. 27(5): p. 606-625.

[36] Li, Q., et al., NSUN2-Mediated m5C Methylation and METTL3/METTL14-Mediated m6A Methylation Cooperatively Enhance p21 Translation. J Cell Biochem, 2017. 118(9): p. 2587-2598.

[37] Blanco, S. and M. Frye, Role of RNA methyltransferases in tissue renewal and pathology. Curr Opin Cell Biol, 2014. 31: p. 1-7.

[38] Khan, M.A., et al., Mutation in NSUN2, which encodes an RNA methyltransferase, causes autosomal-recessive intellectual disability. Am J Hum Genet, 2012. 90(5): p. 856-63.

[39] Martinez, F.J., et al., Whole exome sequencing identifies a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome. J Med Genet, 2012. 49(6): p. 380-5.

[40] Flores, J.V., et al., Cytosine-5 RNA Methylation Regulates Neural Stem Cell Differentiation and Motility. Stem Cell Reports, 2017. 8(1): p. 112-124.

[41] Trixl, L., et al., RNA cytosine methyltransferase Nsun3 regulates embryonic stem cell differentiation by promoting mitochondrial activity. Cell Mol Life Sci, 2018. 75(8): p. 1483-1497.

[42] Chi, L. and P. Delgado-Olguin, Expression of NOL1/NOP2/sun domain (Nsun) RNA methyltransferase family genes in early mouse embryogenesis. Gene Expr Patterns, 2013. 13(8): p. 319-27.

[43] Khosronezhad, N., A.H. Colagar, and S.G. Jorsarayi, T26248G-transversion mutation in exon7 of the putative methyltransferase Nsun7 gene causes a change in protein folding associated with reduced sperm motility in asthenospermic men. Reprod Fertil Dev, 2015. 27(3): p. 471-80.

[44] Doll, A. and K.H. Grzeschik, Characterization of two novel genes, WBSCR20 and WBSCR22, deleted in Williams-Beuren syndrome. Cytogenet Cell Genet, 2001. 95(1-2): p. 20-7.