RNA nucleotide methylation

Methylation of RNA occurs at a variety of atoms, nucleotides, sequences and tertiary structures. Strongly related to other posttranscriptional modifications, methylation of different RNA species includes tRNA, rRNA, mRNA, tmRNA, snRNA, snoRNA, miRNA, and viral RNA. Different catalytic strategies are employed for RNA methylation by a variety of RNA‐methyltransferases which fall into four superfamilies. This review outlines the different functions of methyl groups in RNA, including biophysical, biochemical and metabolic stabilization of RNA, quality control, resistance to antibiotics, mRNA reading frame maintenance, deciphering of normal and altered genetic code, selenocysteine incorporation, tRNA aminoacylation, ribotoxins, splicing, intracellular trafficking, immune response, and others. Connections to other fields including gene regulation, DNA repair, stress response, and possibly histone acetylation and exocytosis are pointed out. WIREs RNA 2011 2 611–631 DOI: 10.1002/wrna.79

[1]  C. Gaspin,et al.  Two different mechanisms for tRNA ribose methylation in Archaea: a short survey. , 2005, Biochimie.

[2]  R Giegé,et al.  A Watson-Crick base-pair-disrupting methyl group (m1A9) is sufficient for cloverleaf folding of human mitochondrial tRNALys. , 1999, Biochemistry.

[3]  P. Agris,et al.  5-Methylcytidine is required for cooperative binding of Mg2+ and a conformational transition at the anticodon stem-loop of yeast phenylalanine tRNA. , 1993, Biochemistry.

[4]  G. Björk,et al.  Three Modifications in the D and T Arms of tRNA Influence Translation in Escherichia coli and Expression of Virulence Genes in Shigella flexneri , 2002, Journal of bacteriology.

[5]  Frank Lyko,et al.  5-methylcytosine in RNA: detection, enzymatic formation and biological functions , 2009, Nucleic acids research.

[6]  P. Farabaugh,et al.  Transfer RNA modifications that alter +1 frameshifting in general fail to affect -1 frameshifting. , 2003, RNA.

[7]  A. Leschziner,et al.  A Dimeric Structure for Archaeal Box C/D Small Ribonucleoproteins , 2009, Science.

[8]  S. Shimba,et al.  Methylated cap structures in eukaryotic RNAs: structure, synthesis and functions. , 1992, Pharmacology & therapeutics.

[9]  C. Branlant,et al.  Posttranscriptional Modifications in the U Small Nuclear RNAs , 1998 .

[10]  M. Tuck The formation of internal 6-methyladenine residues in eucaryotic messenger RNA. , 1992, The International journal of biochemistry.

[11]  V. Cowling,et al.  Regulation of mRNA cap methylation , 2009, The Biochemical journal.

[12]  Jef Rozenski,et al.  The RNA modification database, RNAMDB: 2011 update , 2010, Nucleic Acids Res..

[13]  N. Rajewsky,et al.  A human snoRNA with microRNA-like functions. , 2008, Molecular cell.

[14]  J. Bujnicki,et al.  Molecular phylogenetics and comparative modeling of HEN1, a methyltransferase involved in plant microRNA biogenesis , 2006, BMC Evolutionary Biology.

[15]  E. Phizicky,et al.  Degradation of several hypomodified mature tRNA species in Saccharomyces cerevisiae is mediated by Met22 and the 5'-3' exonucleases Rat1 and Xrn1. , 2008, Genes & development.

[16]  T. Lindahl,et al.  Nonenzymatic methylation of DNA by the intracellular methyl group donor S‐adenosyl‐L‐methionine is a potentially mutagenic reaction. , 1982, The EMBO journal.

[17]  A. Malhotra,et al.  A novel class of small RNAs: tRNA-derived RNA fragments (tRFs). , 2009, Genes & development.

[18]  S. Douthwaite,et al.  Nucleotide methylations in rRNA that confer resistance to ribosome-targeting antibiotics , 2005 .

[19]  J. Ebel,et al.  Conformation in solution of yeast tRNA(Asp) transcripts deprived of modified nucleotides. , 1990, Biochimie.

[20]  Clement T Y Chan,et al.  Human AlkB Homolog ABH8 Is a tRNA Methyltransferase Required for Wobble Uridine Modification and DNA Damage Survival , 2010, Molecular and Cellular Biology.

[21]  Henri Grosjean,et al.  Modification And Editing Of Rna , 1998 .

[22]  Raven H. Huang,et al.  Reconstituting Bacterial RNA Repair and Modification in Vitro , 2009, Science.

[23]  T. Kanai,et al.  N7-Methylguanine at position 46 (m7G46) in tRNA from Thermus thermophilus is required for cell viability at high temperatures through a tRNA modification network , 2009, Nucleic acids research.

[24]  J. Brosius,et al.  Isolation and Posttranscriptional Modification Analysis of Native BC1 RNA from Mouse Brain , 2007, RNA biology.

[25]  G. Nienhaus,et al.  Sculpting an RNA conformational energy landscape by a methyl group modification--a single-molecule FRET study. , 2008, Angewandte Chemie.

[26]  N. Okada,et al.  5-Methylcytidylic modification of in vitro transcript from the rat identifier sequence; evidence that the transcript forms a tRNA-like structure. , 1985, Nucleic acids research.

[27]  Francesca Tuorto,et al.  RNA methylation by Dnmt2 protects transfer RNAs against stress-induced cleavage. , 2010, Genes & development.

[28]  F. Forouhar,et al.  S-Adenosylmethionine-dependent radical-based modification of biological macromolecules. , 2010, Current opinion in structural biology.

[29]  Alan G Hinnebusch,et al.  Nuclear surveillance and degradation of hypomodified initiator tRNAMet in S. cerevisiae. , 2004, Genes & development.

[30]  J. Boothroyd,et al.  Mass spectrometry of mRNA cap 4 from trypanosomatids reveals two novel nucleosides. , 1992, Journal of Biological Chemistry.

[31]  Y. Motorin,et al.  Multisite-specific tRNA:m5C-methyltransferase (Trm4) in yeast Saccharomyces cerevisiae: identification of the gene and substrate specificity of the enzyme. , 1999, RNA.

[32]  J. Perona,et al.  Mechanism of N-methylation by the tRNA m1G37 methyltransferase Trm5. , 2010, RNA.

[33]  C. Florentz,et al.  A pseudoknotted tRNA variant is a substrate for tRNA (cytosine-5)-methyltransferase from Xenopus laevis. , 1998, Biochimie.

[34]  J. Puglisi,et al.  Solution structure of the A loop of 23S ribosomal RNA , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Thomas J. Begley,et al.  Trm9-catalyzed tRNA modifications link translation to the DNA damage response. , 2007, Molecular cell.

[36]  Eugene V Koonin,et al.  SPOUT: a class of methyltransferases that includes spoU and trmD RNA methylase superfamilies, and novel superfamilies of predicted prokaryotic RNA methylases. , 2002, Journal of molecular microbiology and biotechnology.

[37]  K. Watanabe,et al.  Heat-induced stability of tRNA from an extreme thermophile, Thermus thermophilus. , 1976, Biochemical and biophysical research communications.

[38]  H. Myllykallio,et al.  Folate-Dependent Thymidylate-Forming Enzymes: Parallels between DNA and RNA Metabolic Enzymes and Evolutionary Implications , 2013 .

[39]  Mark Helm,et al.  Post-transcriptional nucleotide modification and alternative folding of RNA , 2006, Nucleic acids research.

[40]  P. Agris,et al.  The importance of being modified: roles of modified nucleosides and Mg2+ in RNA structure and function. , 1996, Progress in nucleic acid research and molecular biology.

[41]  G. Grisetti,et al.  Further Reading , 1984, IEEE Spectrum.

[42]  S. K. Mahto,et al.  Expanding the nucleotide repertoire of the ribosome with post-transcriptional modifications. , 2007, ACS chemical biology.

[43]  J. Tazi,et al.  Hypermethylation of the cap structure of both yeast snRNAs and snoRNAs requires a conserved methyltransferase that is localized to the nucleolus. , 2002, Molecular cell.

[44]  Richard Giegé,et al.  The presence of modified nucleotides is required for cloverleaf folding of a human mitochondrial tRNA. , 1998, Nucleic acids research.

[45]  Jef Rozenski,et al.  The RNA Modification Database: 1999 update , 1999, Nucleic Acids Res..

[46]  Justin L Cotney,et al.  Elucidation of separate, but collaborative functions of the rRNA methyltransferase-related human mitochondrial transcription factors B1 and B2 in mitochondrial biogenesis reveals new insight into maternally inherited deafness. , 2009, Human molecular genetics.

[47]  Xuemei Chen,et al.  microRNA biogenesis and function in plants , 2005, FEBS letters.

[48]  B. Berkhout,et al.  A miRNA-tRNA mix-up: tRNA origin of proposed miRNA. , 2010, RNA biology.

[49]  J. Perona,et al.  Stereochemical mechanisms of tRNA methyltransferases , 2010, FEBS letters.

[50]  Wayne A. Decatur,et al.  rRNA modifications and ribosome function. , 2002, Trends in biochemical sciences.

[51]  J. Rousset,et al.  Nucleotide modifications in three functionally important regions of the Saccharomyces cerevisiae ribosome affect translation accuracy , 2009, Nucleic acids research.

[52]  R. Micura,et al.  RNA Two‐State Conformation Equilibria and the Effect of Nucleobase Methylation , 2002 .

[53]  L. H. Hansen,et al.  Identification of 8-methyladenosine as the modification catalyzed by the radical SAM methyltransferase Cfr that confers antibiotic resistance in bacteria. , 2009, RNA.

[54]  Weifeng Gu,et al.  Rapid tRNA decay can result from lack of nonessential modifications. , 2006, Molecular cell.

[55]  J. Bujnicki,et al.  New archaeal methyltransferases forming 1-methyladenosine or 1-methyladenosine and 1-methylguanosine at position 9 of tRNA , 2010, Nucleic acids research.

[56]  J. Bokar The biosynthesis and functional roles of methylated nucleosides in eukaryotic mRNA , 2005 .

[57]  M. Helm,et al.  Nuclear control of cloverleaf structure of human mitochondrial tRNA(Lys). , 2004, Journal of molecular biology.

[58]  Vadim N. Gladyshev,et al.  How Selenium Has Altered Our Understanding of the Genetic Code , 2002, Molecular and Cellular Biology.

[59]  S. Yokoyama,et al.  CD and NMR studies on the conformational thermostability of 2-thioribothymidine found in the T psi C loop of thermophile tRNA. , 1979, Biochemical and biophysical research communications.

[60]  I. Brierley,et al.  Expression of a coronavirus ribosomal frameshift signal in Escherichia coli: influence of tRNA anticodon modification on frameshifting , 1997, Journal of Molecular Biology.

[61]  Piet Herdewijn,et al.  A methyl group controls conformational equilibrium in human mitochondrial tRNA(Lys). , 2007, Journal of the American Chemical Society.

[62]  Maurille J. Fournier,et al.  The 3D rRNA modification maps database: with interactive tools for ribosome analysis , 2007, Nucleic Acids Res..

[63]  M. A. Rubio,et al.  Editing and modification in trypanosomatids: the reshaping of non-coding RNAs , 2005 .

[64]  Li-Ching Hsieh,et al.  Abundance of tRNA-derived small RNAs in phosphate-starved Arabidopsis roots , 2010, Plant signaling & behavior.

[65]  I. Tinoco,et al.  Studies of the conformation of modified dinucleoside phosphates containing 1,N6-ethenoadenosine and 2'-O-methylcytidine by 360-MHz 1H nuclear magnetic resonance spectroscopy. Investigation of the solution conformations of dinucleoside phosphates. , 1977, Biochemistry.

[66]  D. Davis Biophysical and Conformational Properties of Modified Nucleosides in RNA (Nuclear Magnetic Resonance Studies) , 1998 .

[67]  F. Rottman,et al.  N6-adenosine methylation in mRNA: substrate specificity and enzyme complexity. , 1994, Biochimie.

[68]  J. Svejstrup Elongator complex: how many roles does it play? , 2007, Current opinion in cell biology.

[69]  K. Watanabe,et al.  Thermally induced biosynthesis of 2'-O-methylguanosine in tRNA from an extreme thermophile, Thermus thermophilus HB27. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[70]  K. Long,et al.  Antibiotic Resistance in Bacteria Caused by Modified Nucleosides in 23S Ribosomal RNA , 2013 .

[71]  S. K. Purushothaman,et al.  Spb1p-directed formation of Gm2922 in the ribosome catalytic center occurs at a late processing stage. , 2004, Molecular cell.

[72]  D. Weissman,et al.  Naturally occurring nucleoside modifications suppress the immunostimulatory activity of RNA: implication for therapeutic RNA development. , 2007, Current opinion in drug discovery & development.

[73]  Corey Nislow,et al.  Genome-Wide Screen in Saccharomyces cerevisiae Identifies Vacuolar Protein Sorting, Autophagy, Biosynthetic, and tRNA Methylation Genes Involved in Life Span Regulation , 2010, PLoS genetics.

[74]  P. Farabaugh Translational frameshifting: implications for the mechanism of translational frame maintenance. , 2000, Progress in nucleic acid research and molecular biology.

[75]  S. K. Purushothaman,et al.  Trm112p Is a 15-kDa Zinc Finger Protein Essential for the Activity of Two tRNA and One Protein Methyltransferases in Yeast* , 2010, The Journal of Biological Chemistry.

[76]  D. Santi,et al.  The catalytic mechanism and structure of thymidylate synthase. , 1995, Annual review of biochemistry.

[77]  Bo Huang,et al.  An early step in wobble uridine tRNA modification requires the Elongator complex. , 2005, RNA.

[78]  Tsutomu Suzuki,et al.  Temperature-dependent Biosynthesis of 2-Thioribothymidine of Thermus thermophilus tRNA* , 2006, Journal of Biological Chemistry.

[79]  P. Magee,et al.  Nonenzymatic methylation of DNA by S-adenosylmethionine in vitro. , 1982, Carcinogenesis.

[80]  E. Hurt,et al.  Pus1p-dependent tRNA Pseudouridinylation Becomes Essential When tRNA Biogenesis Is Compromised in Yeast* , 2001, The Journal of Biological Chemistry.

[81]  E. Phizicky,et al.  Identification of the yeast gene encoding the tRNA m1G methyltransferase responsible for modification at position 9. , 2003, RNA.

[82]  J. F. Atkins,et al.  A Gripping Tale of Ribosomal Frameshifting: Extragenic Suppressors of Frameshift Mutations Spotlight P-Site Realignment , 2009, Microbiology and Molecular Biology Reviews.

[83]  James A. McCloskey,et al.  The RNA modification database , 1997, Nucleic Acids Res..

[84]  G. Kaufmann Anticodon nucleases. , 2000, Trends in biochemical sciences.

[85]  Henri Grosjean,et al.  Fine-tuning of RNA functions by modification and editing , 2005 .

[86]  G. Björk,et al.  Improvement of reading frame maintenance is a common function for several tRNA modifications , 2001, The EMBO journal.

[87]  G. Shadel Coupling the mitochondrial transcription machinery to human disease. , 2004, Trends in genetics : TIG.

[88]  S. Yokoyama,et al.  Two tRNAIle1 species from an extreme thermophile, Thermus thermophilus HB8: effect of 2-thiolation of ribothymidine on the thermostability of tRNA. , 1985, Biochemistry.

[89]  Gabriele Varani,et al.  The structure and function of small nucleolar ribonucleoproteins , 2007, Nucleic acids research.

[90]  J. Bachellerie,et al.  Guiding ribose methylation of rRNA. , 1997, Trends in biochemical sciences.

[91]  R. Micura,et al.  Bistable secondary structures of small RNAs and their structural probing by comparative imino proton NMR spectroscopy. , 2003, Journal of molecular biology.

[92]  A. Byström,et al.  The Kluyveromyces lactis γ-toxin targets tRNA anticodons , 2005 .

[93]  C. Daniels,et al.  Structure and function of archaeal box C/D sRNP core proteins , 2003, Nature Structural Biology.

[94]  J. Poehlsgaard,et al.  Macrolide antibiotic interaction and resistance on the bacterial ribosome. , 2003, Current opinion in investigational drugs.

[95]  Clement T Y Chan,et al.  A Quantitative Systems Approach Reveals Dynamic Control of tRNA Modifications during Cellular Stress , 2010, PLoS genetics.

[96]  J. F. Atkins,et al.  Presence and location of modified nucleotides in Escherichia coli tmRNA: structural mimicry with tRNA acceptor branches , 1998, The EMBO journal.

[97]  K. Heeg,et al.  Modifications in Small Interfering RNA That Separate Immunostimulation from RNA Interference1 , 2008, The Journal of Immunology.

[98]  R. Cedergren,et al.  A correlation between N2-dimethylguanosine presence and alternate tRNA conformers. , 1995, RNA.

[99]  Marcin Feder,et al.  MODOMICS: a database of RNA modification pathways , 2005, Nucleic Acids Res..

[100]  J. Armengaud,et al.  Identity elements required for enzymatic formation of N2,N2-dimethylguanosine from N2-monomethylated derivative and its possible role in avoiding alternative conformations in archaeal tRNA. , 2006, Journal of molecular biology.

[101]  J. Bujnicki,et al.  Cloning and characterization of tRNA (m1A58) methyltransferase (TrmI) from Thermus thermophilus HB27, a protein required for cell growth at extreme temperatures. , 2003, Nucleic acids research.

[102]  H. Myllykallio,et al.  Identification of a novel gene encoding a flavin-dependent tRNA:m5U methyltransferase in bacteria—evolutionary implications , 2005, Nucleic acids research.

[103]  Michael Agostino Practical Bioinformatics , 2012 .

[104]  G. Björk Genetic dissection of synthesis and function of modified nucleosides in bacterial transfer RNA. , 1995, Progress in nucleic acid research and molecular biology.

[105]  C. Florentz,et al.  Aminoacylation properties of pathology-related human mitochondrial tRNA(Lys) variants. , 2004, RNA.

[106]  Xiaoyu Zhang,et al.  Methylation of tRNAAsp by the DNA Methyltransferase Homolog Dnmt2 , 2006, Science.

[107]  O. Namy,et al.  Translational Recoding and RNA Modifications , 2005, Fine-Tuning of RNA Functions by Modification and Editing.

[108]  V. de Crécy-Lagard,et al.  Biosynthesis of wyosine derivatives in tRNA: an ancient and highly diverse pathway in Archaea. , 2010, Molecular biology and evolution.

[109]  Houping Ni,et al.  Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. , 2005, Immunity.

[110]  M. Helm,et al.  tRNA stabilization by modified nucleotides. , 2010, Biochemistry.

[111]  D. Söll,et al.  The effect of growth temperatures on the in vivo ribose methylation of Bacillus stearothermophilus transfer RNA. , 1973, Archives of biochemistry and biophysics.

[112]  R. Marquet Importance of Modified Nucleotides in Replication of Retroviruses, Plant Pararetroviruses, and Retrotransposons , 1998 .

[113]  M. Helm,et al.  Detection of RNA modifications , 2010, RNA biology.

[114]  S. Yokoyama,et al.  Dynamic structures and functions of transfer ribonucleic acids from extreme thermophiles. , 1987, Advances in biophysics.

[115]  M. Sekine,et al.  Conformational rigidity of specific pyrimidine residues in tRNA arises from posttranscriptional modifications that enhance steric interaction between the base and the 2'-hydroxyl group. , 1992, Biochemistry.

[116]  Janusz M. Bujnicki,et al.  Structural and evolutionary bioinformatics of the SPOUT superfamily of methyltransferases , 2007, BMC Bioinformatics.

[117]  J. Rabinowitz,et al.  Biosynthesis of ribosylthymine in the transfer RNA of Streptococcus faecalis: a folate-dependent methylation not involving S-adenosylmethionine. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[118]  Thoru Pederson,et al.  Regulatory RNAs derived from transfer RNA? , 2010, RNA.

[119]  Janusz M. Bujnicki,et al.  Bioinformatics-Guided Identification and Experimental Characterization of Novel RNA Methyltransferas , 2008 .

[120]  R. Schaffrath,et al.  tRNAGlu wobble uridine methylation by Trm9 identifies Elongator's key role for zymocin‐induced cell death in yeast , 2006, Molecular microbiology.

[121]  Maurille J. Fournier,et al.  RNA-guided Nucleotide Modification of Ribosomal and Other RNAs* , 2003, The Journal of Biological Chemistry.

[122]  Pavel Ivanov,et al.  Angiogenin-induced tRNA-derived Stress-induced RNAs Promote Stress-induced Stress Granule Assembly* , 2010, The Journal of Biological Chemistry.

[123]  Joanna M. Kasprzak,et al.  MODOMICS: a database of RNA modification pathways. 2008 update , 2008, Nucleic acids research.

[124]  J. Kowalak,et al.  The role of posttranscriptional modification in stabilization of transfer RNA from hyperthermophiles. , 1994, Biochemistry.

[125]  J. Bachellerie,et al.  Targeted ribose methylation of RNA in vivo directed by tailored antisense RNA guides , 1996, Nature.

[126]  Janusz M. Bujnicki,et al.  Trm11p and Trm112p Are both Required for the Formation of 2-Methylguanosine at Position 10 in Yeast tRNA , 2005, Molecular and Cellular Biology.

[127]  C. Florentz,et al.  A single methyl group prevents the mischarging of a tRNA , 1994, Nature Structural Biology.

[128]  O. Uhlenbeck,et al.  Biochemical and physical characterization of an unmodified yeast phenylalanine transfer RNA transcribed in vitro. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[129]  Tamás Kiss,et al.  Site-Specific Ribose Methylation of Preribosomal RNA: A Novel Function for Small Nucleolar RNAs , 1996, Cell.

[130]  O. Uhlenbeck,et al.  Structure of an unmodified tRNA molecule. , 1989, Biochemistry.

[131]  Paul F Agris,et al.  tRNA's wobble decoding of the genome: 40 years of modification. , 2007, Journal of molecular biology.

[132]  T. Bestor,et al.  Eukaryotic cytosine methyltransferases. , 2005, Annual review of biochemistry.

[133]  F. Meinhardt,et al.  The primary target of the killer toxin from Pichia acaciae is tRNAGln , 2008, Molecular microbiology.