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N6-Methyladenine: A Conserved and Dynamic DNA Mark

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DNA Methyltransferases - Role and Function

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 945))

Abstract

Chromatin, consisting of deoxyribonucleic acid (DNA) wrapped around histone proteins, facilitates DNA compaction and allows identical DNA codes to confer many different cellular phenotypes. This biological versatility is accomplished in large part by posttranslational modifications to histones and chemical modifications to DNA. These modifications direct the cellular machinery to expand or compact specific chromatin regions and mark regions of the DNA as important for cellular functions. While each of the four bases that make up DNA can be modified (Iyer et al. 2011), this chapter will focus on methylation of the sixth position on adenines (6mA), as this modification has been poorly characterized in recently evolved eukaryotes, but shows promise as a new conserved layer of epigenetic regulation. 6mA was previously thought to be restricted to unicellular organisms, but recent work has revealed its presence in metazoa. Here, we will briefly describe the history of 6mA, examine its evolutionary conservation, and evaluate the current methods for detecting 6mA. We will discuss the enzymes that bind and regulate this mark and finally examine known and potential functions of 6mA in eukaryotes.

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References

  • Aas PA, Otterlei M, Falnes PO, Vagbo CB, Skorpen F, Akbari M, et al. Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA. Nature. 2003;421(6925):859–63. doi:10.1038/nature01363.

    Article  CAS  PubMed  Google Scholar 

  • Achwal CW, Iyer CA, Chandra HS. Immunochemical evidence for the presence of 5mC, 6mA and 7mG in human, Drosophila and mealybug DNA. FEBS Lett. 1983;158(2):353–8.

    Article  CAS  PubMed  Google Scholar 

  • Adams RL, McKay EL, Craig LM, Burdon RH. Methylation of mosquito DNA. Biochim Biophys Acta. 1979;563(1):72–81.

    Article  CAS  PubMed  Google Scholar 

  • Allamane S, Jourdes P, Ratel D, Vicat JM, Dupre I, Laine M, et al. Bacterial DNA methylation and gene transfer efficiency. Biochem Biophys Res Commun. 2000;276(3):1261–4. doi:10.1006/bbrc.2000.3603.

    Article  CAS  PubMed  Google Scholar 

  • Allan BW, Beechem JM, Lindstrom WM, Reich NO. Direct real time observation of base flipping by the EcoRI DNA methyltransferase. J Biol Chem. 1998;273(4):2368–73.

    Article  CAS  PubMed  Google Scholar 

  • Ammermann D, Steinbruck G, Baur R, Wohlert H. Methylated bases in the DNA of the ciliate Stylonychia mytilus. Eur J Cell Biol. 1981;24(1):154–6.

    CAS  PubMed  Google Scholar 

  • Aravind L, Zhang D, Iyer LM. The TET/JBP family of nucleic acid base-modifying 2-oxoglutarate and iron-dependent dioxygenases. In: Hausinger R, Schofield C, editors. 2-oxoglutarate-dependent oxygenases. Royal Society of Chemistry; 2015;3(12);289.

    Google Scholar 

  • Babinger P, Kobl I, Mages W, Schmitt R. A link between DNA methylation and epigenetic silencing in transgenic Volvox carteri. Nucleic Acids Res. 2001;29(6):1261–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bakker A, Smith DW. Methylation of GATC sites is required for precise timing between rounds of DNA replication in Escherichia coli. J Bacteriol. 1989;171(10):5738–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Batista PJ, Molinie B, Wang J, Qu K, Zhang J, Li L, et al. m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell. 2014;15(6):707–19. doi:10.1016/j.stem.2014.09.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berdis AJ, Lee I, Coward JK, Stephens C, Wright R, Shapiro L, et al. A cell cycle-regulated adenine DNA methyltransferase from Caulobacter crescentus processively methylates GANTC sites on hemimethylated DNA. Proc Natl Acad Sci U S A. 1998;95(6):2874–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bestor TH. The DNA, methyltransferases of mammals. Hum Mol Genet. 2000;9(16):2395–402.

    Article  CAS  PubMed  Google Scholar 

  • Bestor T, Laudano A, Mattaliano R, Ingram V. Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases. J Mol Biol. 1988;203(4):971–83.

    Article  CAS  PubMed  Google Scholar 

  • Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002;16(1):6–21. doi:10.1101/gad.947102.

    Article  CAS  PubMed  Google Scholar 

  • Bird AP, Southern EM. Use of restriction enzymes to study eukaryotic DNA methylation: I. The methylation pattern in ribosomal DNA from Xenopus laevis. J Mol Biol. 1978;118(1):27–47.

    Article  CAS  PubMed  Google Scholar 

  • Bodi Z, Zhong S, Mehra S, Song J, Graham N, Li H, et al. Adenosine methylation in Arabidopsis mRNA is associated with the 3′ end and reduced levels cause developmental defects. Front Plant Sci. 2012;3:48. doi:10.3389/fpls.2012.00048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boye E, Lobner-Olesen A. The role of dam methyltransferase in the control of DNA replication in E. coli. Cell. 1990;62(5):981–9.

    Article  CAS  PubMed  Google Scholar 

  • Breiling A, Lyko F. Epigenetic regulatory functions of DNA modifications: 5-methylcytosine and beyond. Epigenetics Chromatin. 2015;8:24. doi:10.1186/s13072-015-0016-6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Brendler T, Abeles A, Austin S. A protein that binds to the P1 origin core and the oriC 13mer region in a methylation-specific fashion is the product of the host seqA gene. EMBO J. 1995;14(16):4083–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bromberg S, Pratt K, Hattman S. Sequence specificity of DNA adenine methylase in the protozoan Tetrahymena thermophila. J Bacteriol. 1982;150(2):993–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Campbell JL, Kleckner N. E. coli oriC and the dnaA gene promoter are sequestered from dam methyltransferase following the passage of the chromosomal replication fork. Cell. 1990;62(5):967–79.

    Article  CAS  PubMed  Google Scholar 

  • Capowski EE, Wells JM, Harrison GS, Karrer KM. Molecular analysis of N6-methyladenine patterns in Tetrahymena thermophila nuclear DNA. Mol Cell Biol. 1989;9(6):2598–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Capuano F, Mulleder M, Kok R, Blom HJ, Ralser M. Cytosine DNA methylation is found in Drosophila melanogaster but absent in Saccharomyces cerevisiae, Schizosaccharomyces pombe, and other yeast species. Anal Chem. 2014;86(8):3697–702. doi:10.1021/ac500447w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Casadesus J, Low D. Epigenetic gene regulation in the bacterial world. Microbiol Mol Biol Rev. 2006;70(3):830–56. doi:10.1128/MMBR.00016-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen K, Luo GZ, He C. High-resolution mapping of N(6)-methyladenosine in transcriptome and genome using a photo-crosslinking-assisted strategy. Methods Enzymol. 2015;560:161–85. doi:10.1016/bs.mie.2015.03.012.

    Article  CAS  PubMed  Google Scholar 

  • Cheng SC, Herman G, Modrich P. Extent of equilibrium perturbation of the DNA helix upon enzymatic methylation of adenine residues. J Biol Chem. 1985;260(1):191–4.

    CAS  PubMed  Google Scholar 

  • Chiang PK, Gordon RK, Tal J, Zeng GC, Doctor BP, Pardhasaradhi K, et al. S-Adenosylmethionine and methylation. FASEB J. 1996;10(4):471–80.

    CAS  PubMed  Google Scholar 

  • Clancy MJ, Shambaugh ME, Timpte CS, Bokar JA. Induction of sporulation in Saccharomyces cerevisiae leads to the formation of N6-methyladenosine in mRNA: a potential mechanism for the activity of the IME4 gene. Nucleic Acids Res. 2002;30(20):4509–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collier J, McAdams HH, Shapiro L. A DNA methylation ratchet governs progression through a bacterial cell cycle. Proc Natl Acad Sci U S A. 2007;104(43):17111–6. doi:10.1073/pnas.0708112104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collins M, Myers RM. Alterations in DNA helix stability due to base modifications can be evaluated using denaturing gradient gel electrophoresis. J Mol Biol. 1987;198(4):737–44.

    Article  CAS  PubMed  Google Scholar 

  • Cummings DJ, Tait A, Goddard JM. Methylated bases in DNA from Paramecium aurelia. Biochim Biophys Acta. 1974;374(1):1–11.

    Article  CAS  PubMed  Google Scholar 

  • Degnen ST, Morris NR. Deoxyribonucleic acid methylation and development in Caulobacter bacteroides. J Bacteriol. 1973;116(1):48–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Delk AS, Rabinowitz JC. Biosynthesis of ribosylthymine in the transfer RNA of Streptococcus faecalis: a folate-dependent methylation not involving S-adenosylmethionine. Proc Natl Acad Sci U S A. 1975;72(2):528–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Delk AS, Romeo JM, Nagle Jr DP, Rabinowitz JC. Biosynthesis of ribothymidine in the transfer RNA of Streptococcus faecalis and Bacillus subtilis. A methylation of RNA involving 5,10-methylenetetrahydrofolate. J Biol Chem. 1976;251(23):7649–56.

    CAS  PubMed  Google Scholar 

  • Deng X, Chen K, Luo GZ, Weng X, Ji Q, Zhou T, et al. Widespread occurrence of N6-methyladenosine in bacterial mRNA. Nucleic Acids Res. 2015;43(13):6557–67. doi:10.1093/nar/gkv596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Diekmann S. DNA methylation can enhance or induce DNA curvature. EMBO J. 1987;6(13):4213–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dohno C, Shibata T, Nakatani K. Discrimination of N6-methyl adenine in a specific DNA sequence. Chem Commun (Camb). 2010;46(30):5530–2. doi:10.1039/c0cc00172d.

    Article  CAS  Google Scholar 

  • Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012;485(7397):201–6. doi:10.1038/nature11112.

    Article  CAS  PubMed  Google Scholar 

  • Drozdz M, Piekarowicz A, Bujnicki JM, Radlinska M. Novel non-specific DNA adenine methyltransferases. Nucleic Acids Res. 2012;40(5):2119–30. doi:10.1093/nar/gkr1039.

    Article  CAS  PubMed  Google Scholar 

  • Du J, Zhong X, Bernatavichute YV, Stroud H, Feng S, Caro E, et al. Dual binding of chromomethylase domains to H3K9me2-containing nucleosomes directs DNA methylation in plants. Cell. 2012;151(1):167–80. doi:10.1016/j.cell.2012.07.034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duncan T, Trewick SC, Koivisto P, Bates PA, Lindahl T, Sedgwick B. Reversal of DNA alkylation damage by two human dioxygenases. Proc Natl Acad Sci U S A. 2002;99(26):16660–5. doi:10.1073/pnas.262589799.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dunn DB, Smith JD. Occurrence of a new base in the deoxyribonucleic acid of a strain of Bacterium coli. Nature. 1955;175(4451):336–7.

    Article  CAS  PubMed  Google Scholar 

  • Dunn DB, Smith JD. The occurrence of 6-methylaminopurine in deoxyribonucleic acids. Biochem J. 1958;68(4):627–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ehrlich M, Gama-Sosa MA, Huang LH, Midgett RM, Kuo KC, McCune RA, et al. Amount and distribution of 5-methylcytosine in human DNA from different types of tissues of cells. Nucleic Acids Res. 1982;10(8):2709–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ehrlich M, Gama-Sosa MA, Carreira LH, Ljungdahl LG, Kuo KC, Gehrke CW. DNA methylation in thermophilic bacteria: N4-methylcytosine, 5-methylcytosine, and N6-methyladenine. Nucleic Acids Res. 1985;13(4):1399–412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ehrlich M, Wilson GG, Kuo KC, Gehrke CW. N4-methylcytosine as a minor base in bacterial DNA. J Bacteriol. 1987;169(3):939–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Engel JD, von Hippel PH. D(M6ATP) as a probe of the fidelity of base incorporation into polynucleotides by Escherichia coli DNA polymerase I. J Biol Chem. 1978a;253(3):935–9.

    CAS  PubMed  Google Scholar 

  • Engel JD, von Hippel PH. Effects of methylation on the stability of nucleic acid conformations. Studies at the polymer level. J Biol Chem. 1978b;253(3):927–34.

    CAS  PubMed  Google Scholar 

  • Falnes PO, Johansen RF, Seeberg E. AlkB-mediated oxidative demethylation reverses DNA damage in Escherichia coli. Nature. 2002;419(6903):178–82. doi:10.1038/nature01048.

    Article  CAS  PubMed  Google Scholar 

  • Fazakerley GV, Guy A, Teoule R, Quignard E, Guschlbauer W. A proton 2D-NMR study of an oligodeoxyribonucleotide containing N6-methyladenine:d(GGm6ATATCC). Biochimie. 1985;67(7–8):819–22.

    Article  CAS  PubMed  Google Scholar 

  • Fazakerley GV, Quignard E, Teoule R, Guy A, Guschlbauer W. A two-dimensional 1H-NMR study of the dam methylase site: comparison between the hemimethylated GATC sequence, its unmethylated analogue and a hemimethylated CATG sequence. The sequence dependence of methylation upon base-pair lifetimes. Eur J Biochem. 1987;167(3):397–404.

    Article  CAS  PubMed  Google Scholar 

  • Fazakerley GV, Gabarro-Arpa J, Lebret M, Guy A, Guschlbauer W. The GTm6AC sequence is overwound and bent. Nucleic Acids Res. 1989;17(7):2541–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fedeles BI, Singh V, Delaney JC, Li D, Essigmann JM. The AlkB family of Fe(II)/alpha-ketoglutarate-dependent dioxygenases: repairing nucleic acid alkylation damage and beyond. J Biol Chem. 2015;290(34):20734–42. doi:10.1074/jbc.R115.656462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fleissner E, Borek E. A new enzyme of RNA synthesis: RNA methylase. Proc Natl Acad Sci U S A. 1962;48:1199–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Flusberg BA, Webster DR, Lee JH, Travers KJ, Olivares EC, Clark TA, et al. Direct detection of DNA methylation during single-molecule, real-time sequencing. Nat Methods. 2010;7(6):461–5. doi:10.1038/nmeth.1459.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fu Y, Jia G, Pang X, Wang RN, Wang X, Li CJ, et al. FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA. Nat Commun. 2013;4:1798. doi:10.1038/ncomms2822.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fu Y, Luo GZ, Chen K, Deng X, Yu M, Han D, et al. N(6)-methyldeoxyadenosine marks active transcription start sites in chlamydomonas. Cell. 2015;161(4):879–92. doi:10.1016/j.cell.2015.04.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujikawa N, Kurumizaka H, Nureki O, Tanaka Y, Yamazoe M, Hiraga S, et al. Structural and biochemical analyses of hemimethylated DNA binding by the SeqA protein. Nucleic Acids Res. 2004;32(1):82–92. doi:10.1093/nar/gkh173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gama-Sosa MA, Midgett RM, Slagel VA, Githens S, Kuo KC, Gehrke CW, et al. Tissue-specific differences in DNA methylation in various mammals. Biochim Biophys Acta. 1983;740(2):212–9.

    Article  CAS  PubMed  Google Scholar 

  • Geier GE, Modrich P. Recognition sequence of the dam methylase of Escherichia coli K12 and mode of cleavage of Dpn I endonuclease. J Biol Chem. 1979;254(4):1408–13.

    CAS  PubMed  Google Scholar 

  • Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS, et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science (New York, NY). 2007;318(5855):1469–72. doi:10.1126/science.1151710.

    Article  CAS  Google Scholar 

  • Glickman BW. Spontaneous mutagenesis in Escherichia coli strains lacking 6-methyladenine residues in their DNA: an altered mutational spectrum in dam- mutants. Mutat Res. 1979;61(2):153–62.

    Article  CAS  PubMed  Google Scholar 

  • Glickman B, van den Elsen P, Radman M. Induced mutagenesis in dam- mutants of Escherichia coli: a role for 6-methyladenine residues in mutation avoidance. Mol Gen Genet. 1978;163(3):307–12.

    Article  CAS  PubMed  Google Scholar 

  • Goedecke K, Pignot M, Goody RS, Scheidig AJ, Weinhold E. Structure of the N6-adenine DNA methyltransferase M.TaqI in complex with DNA and a cofactor analog. Nat Struct Biol. 2001;8(2):121–5. doi:10.1038/84104.

    Article  CAS  PubMed  Google Scholar 

  • Gold M, Hurwitz J. The enzymatic methylation of ribonucleic acid and deoxyribonucleic acid. V. Purification and properties of the deoxyribonucleic acid-methylating activity of Escherichia Coli. J Biol Chem. 1964;239:3858–65.

    CAS  PubMed  Google Scholar 

  • Gold M, Hurwitz J, Anders M. The enzymatic methylation of RNA and DNA. Biochem Biophys Res Commun. 1963;11:107–14.

    Article  CAS  PubMed  Google Scholar 

  • Gommers-Ampt JH, Borst P. Hypermodified bases in DNA. FASEB J. 1995;9(11):1034–42.

    CAS  PubMed  Google Scholar 

  • Gommers-Ampt JH, Van Leeuwen F, de Beer AL, Vliegenthart JF, Dizdaroglu M, Kowalak JA, et al. beta-D-glucosyl-hydroxymethyluracil: a novel modified base present in the DNA of the parasitic protozoan T. brucei. Cell. 1993;75(6):1129–36.

    Article  CAS  PubMed  Google Scholar 

  • Gorovsky MA, Hattman S, Pleger GL. (6 N)methyl adenine in the nuclear DNA of a eucaryote, Tetrahymena pyriformis. J Cell Biol. 1973;56(3):697–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Graham MW, Larkin PJ. Adenine methylation at dam sites increases transient gene expression in plant cells. Transgenic Res. 1995;4(5):324–31.

    Article  CAS  PubMed  Google Scholar 

  • Greer EL, Beese-Sims SE, Brookes E, Spadafora R, Zhu Y, Rothbart SB, et al. A histone methylation network regulates transgenerational epigenetic memory in C. elegans. Cell Rep. 2014;7(1):113–26. doi:10.1016/j.celrep.2014.02.044.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greer EL, Becker B, Latza C, Antebi A, Shi Y. Mutation of C. elegans demethylase spr-5 extends transgenerational longevity. Cell Res. 2016;26(2):229–38. doi:10.1038/cr.2015.148.

    Google Scholar 

  • Greer EL, Blanco MA, Gu L, Sendinc E, Liu J, Aristizabal-Corrales D, et al. DNA Methylation on N(6)-Adenine in C. elegans. Cell. 2015b;161(4):868–78. doi:10.1016/j.cell.2015.04.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grosjean H. Nucleic acids are not boring long polymers of only four types of nucleotides: a guided tour. In: Grosjean H, editor. DNA and RNA modi cation enzymes: structure, mechanism, function and evolution. New York: CRC Press; 2009. p. 1–18.

    Google Scholar 

  • Grosjean H. RNA modification: the Golden Period 1995–2015. RNA. 2015;21(4):625–6. doi:10.1261/rna.049866.115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guarne A, Zhao Q, Ghirlando R, Yang W. Insights into negative modulation of E. coli replication initiation from the structure of SeqA-hemimethylated DNA complex. Nat Struct Biol. 2002;9(11):839–43. doi:10.1038/nsb857.

    CAS  PubMed  Google Scholar 

  • Hagerman KR, Hagerman PJ. Helix rigidity of DNA: the meroduplex as an experimental paradigm. J Mol Biol. 1996;260(2):207–23. doi:10.1006/jmbi.1996.0393.

    Article  CAS  PubMed  Google Scholar 

  • Hassel M, Cornelius MG, Vom Brocke J, Schmeiser HH. Total nucleotide analysis of Hydra DNA and RNA by MEKC with LIF detection and 32P-postlabeling. Electrophoresis. 2010;31(2):299–302. doi:10.1002/elps.200900458.

    Article  CAS  PubMed  Google Scholar 

  • Hattman S, Kenny C, Berger L, Pratt K. Comparative study of DNA methylation in three unicellular eucaryotes. J Bacteriol. 1978;135(3):1156–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Heindell HC, Liu A, Paddock GV, Studnicka GM, Salser WA. The primary sequence of rabbit alpha-globin mRNA. Cell. 1978;15(1):43–54.

    Article  CAS  PubMed  Google Scholar 

  • Hongay CF, Orr-Weaver TL. Drosophila Inducer of MEiosis 4 (IME4) is required for Notch signaling during oogenesis. Proc Natl Acad Sci U S A. 2011;108(36):14855–60. doi:10.1073/pnas.1111577108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horton JR, Liebert K, Hattman S, Jeltsch A, Cheng X. Transition from nonspecific to specific DNA interactions along the substrate-recognition pathway of dam methyltransferase. Cell. 2005;121(3):349–61. doi:10.1016/j.cell.2005.02.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horton JR, Liebert K, Bekes M, Jeltsch A, Cheng X. Structure and substrate recognition of the Escherichia coli DNA adenine methyltransferase. J Mol Biol. 2006;358(2):559–70. doi:10.1016/j.jmb.2006.02.028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hotchkiss RD. The quantitative separation of purines, pyrimidines, and nucleosides by paper chromatography. J Biol Chem. 1948;175(1):315–32.

    CAS  PubMed  Google Scholar 

  • Huang W, Xiong J, Yang Y, Liu SM, Yuan BF, Feng YQ. Determination of DNA adenine methylation in genomes of mammals and plants by liquid chromatography/mass spectrometry. Royal Soc Chem Adv. 2015;5:64046–54.

    CAS  Google Scholar 

  • Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010;466(7310):1129–33. doi:10.1038/nature09303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science (New York, NY). 2011;333(6047):1300–3. doi:10.1126/science.1210597.

    Article  CAS  Google Scholar 

  • Iyer LM, Abhiman S, Aravind L. Natural history of eukaryotic DNA methylation systems. Prog Mol Biol Transl Sci. 2011;101:25–104. doi:10.1016/B978-0-12-387685-0.00002-0.

    Article  CAS  PubMed  Google Scholar 

  • Jabbari K, Caccio S, Pais de Barros JP, Desgres J, Bernardi G. Evolutionary changes in CpG and methylation levels in the genome of vertebrates. Gene. 1997;205(1–2):109–18.

    Article  CAS  PubMed  Google Scholar 

  • Jackson JP, Lindroth AM, Cao X, Jacobsen SE. Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase. Nature. 2002;416(6880):556–60. doi:10.1038/nature731.

    Article  CAS  PubMed  Google Scholar 

  • Janulaitis A, Klimasauskas S, Petrusyte M, Butkus V. Cytosine modification in DNA by BcnI methylase yields N4-methylcytosine. FEBS Lett. 1983;161(1):131–4.

    Article  CAS  PubMed  Google Scholar 

  • Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 2011;7(12):885–7. doi:10.1038/nchembio.687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson TB, Coghill RD. The discovery of 5-methyl-cytosine in tuberculinic acid, the nucleic acid of the Tubercle bacillus. J Am Chem Soc. 1925;47:2838–44.

    Article  CAS  Google Scholar 

  • Johnson LM, Bostick M, Zhang X, Kraft E, Henderson I, Callis J, et al. The SRA methyl-cytosine-binding domain links DNA and histone methylation. Curr Biol. 2007;17(4):379–84. doi:10.1016/j.cub.2007.01.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet. 2012;13(7):484–92. doi:10.1038/nrg3230.

    Article  CAS  PubMed  Google Scholar 

  • Kakutani T, Munakata K, Richards EJ, Hirochika H. Meiotically and mitotically stable inheritance of DNA hypomethylation induced by ddm1 mutation of Arabidopsis thaliana. Genetics. 1999;151(2):831–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kamat SS, Fan H, Sauder JM, Burley SK, Shoichet BK, Sali A, et al. Enzymatic deamination of the epigenetic base N-6-methyladenine. J Am Chem Soc. 2011;133(7):2080–3. doi:10.1021/ja110157u.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karrer KM, VanNuland TA. Methylation of adenine in the nuclear DNA of Tetrahymena is internucleosomal and independent of histone H1. Nucleic Acids Res. 2002;30(6):1364–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Katz DJ, Edwards TM, Reinke V, Kelly WG. A C. elegans LSD1 demethylase contributes to germline immortality by reprogramming epigenetic memory. Cell. 2009;137(2):308–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kornberg A, Zimmerman SB, Kornberg SR, Josse J. Enzymatic synthesis of deoxyribonucleic acid. Influence of bacteriophage T2 on the synthetic pathway in host cells. Proc Natl Acad Sci U S A. 1959;45(6):772–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kornberg SR, Zimmerman SB, Kornberg A. Glucosylation of deoxyribonucleic acid by enzymes from bacteriophage-infected Escherichia coli. J Biol Chem. 1961;236:1487–93.

    CAS  PubMed  Google Scholar 

  • Kozdon JB, Melfi MD, Luong K, Clark TA, Boitano M, Wang S, et al. Global methylation state at base-pair resolution of the Caulobacter genome throughout the cell cycle. Proc Natl Acad Sci U S A. 2013;110(48):E4658–67. doi:10.1073/pnas.1319315110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koziol MJ, Bradshaw CR, Allen GE, Costa AS, Frezza C, Gurdon JB. Identification of methylated deoxyadenosines in vertebrates reveals diversity in DNA modifications. Nat Struct Mol Biol. 2016;23(1):24–30. doi:10.1038/nsmb.3145.

    Article  CAS  PubMed  Google Scholar 

  • Krais AM, Cornelius MG, Schmeiser HH. Genomic N(6)-methyladenine determination by MEKC with LIF. Electrophoresis. 2010;31(21):3548–51. doi:10.1002/elps.201000357.

    Article  CAS  PubMed  Google Scholar 

  • Lahue RS, Su SS, Modrich P. Requirement for d(GATC) sequences in Escherichia coli mutHLS mismatch correction. Proc Natl Acad Sci U S A. 1987;84(6):1482–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Letunic I, Bork P. Interactive tree of life v2: online annotation and display of phylogenetic trees made easy. Nucleic Acids Res. 2011;39(Web Server issue):W475–8. doi:10.1093/nar/gkr201.

    Google Scholar 

  • Lichtsteiner S, Schibler U. A glycosylated liver-specific transcription factor stimulates transcription of the albumin gene. Cell. 1989;57(7):1179–87.

    Article  CAS  PubMed  Google Scholar 

  • Lindahl T, Nyberg B. Heat-induced deamination of cytosine residues in deoxyribonucleic acid. Biochemistry. 1974;13(16):3405–10.

    Article  CAS  PubMed  Google Scholar 

  • Linn S, Arber W. Host specificity of DNA produced by Escherichia coli, X. In vitro restriction of phage fd replicative form. Proc Natl Acad Sci U S A. 1968;59(4):1300–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 2014;10(2):93–5. doi:10.1038/nchembio.1432.

    Article  CAS  PubMed  Google Scholar 

  • Low DA, Weyand NJ, Mahan MJ. Roles of DNA adenine methylation in regulating bacterial gene expression and virulence. Infect Immun. 2001;69(12):7197–204. doi:10.1128/IAI.69.12.7197-7204.2001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu M, Campbell JL, Boye E, Kleckner N. SeqA: a negative modulator of replication initiation in E. coli. Cell. 1994;77(3):413–26.

    Article  CAS  PubMed  Google Scholar 

  • Luo GZ, Blanco MA, Greer EL, He C, Shi Y. DNA N-methyladenine: a new epigenetic mark in eukaryotes? Nat Rev. 2015;16(12):705–10. doi:10.1038/nrm4076.

    Article  CAS  Google Scholar 

  • Luria SE, Human ML. A nonhereditary, host-induced variation of bacterial viruses. J Bacteriol. 1952;64(4):557–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lyko F, Ramsahoye BH, Jaenisch R. DNA methylation in Drosophila melanogaster. Nature. 2000;408(6812):538–40. doi:10.1038/35046205.

    Article  CAS  PubMed  Google Scholar 

  • Machnicka MA, Milanowska K, Osman Oglou O, Purta E, Kurkowska M, Olchowik A, et al. MODOMICS: a database of RNA modification pathways--2013 update. Nucleic Acids Res. 2013;41(Database issue):D262–7. doi:10.1093/nar/gks1007.

    Article  CAS  PubMed  Google Scholar 

  • Macon JB, Wolfenden R. 1-Methyladenosine. Dimroth rearrangement and reversible reduction. Biochemistry. 1968;7(10):3453–8.

    Article  CAS  PubMed  Google Scholar 

  • Malagnac F, Bartee L, Bender J. An Arabidopsis SET domain protein required for maintenance but not establishment of DNA methylation. EMBO J. 2002;21(24):6842–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malygin EG, Lindstrom Jr WM, Schlagman SL, Hattman S, Reich NO. Pre-steady state kinetics of bacteriophage T4 dam DNA-[N(6)-adenine] methyltransferase: interaction with native (GATC) or modified sites. Nucleic Acids Res. 2000;28(21):4207–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marinus MG. Adenine methylation of Okazaki fragments in Escherichia coli. J Bacteriol. 1976;128(3):853–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Marinus MG, Lobner-Olesen A. DNA methylation. Ecosal Plus. 2014;6(1). doi:10.1128/ecosalplus.ESP-0003-2013.

  • Marinus MG, Morris NR. Isolation of deoxyribonucleic acid methylase mutants of Escherichia coli K-12. J Bacteriol. 1973;114(3):1143–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Marinus MG, Morris NR. Biological function for 6-methyladenine residues in the DNA of Escherichia coli K12. J Mol Biol. 1974;85(2):309–22.

    Article  CAS  PubMed  Google Scholar 

  • Martin C, Zhang Y. Mechanisms of epigenetic inheritance. Curr Opin Cell Biol. 2007;19(3):266–72. S0955-0674(07)00054-3 [pii]. doi:10.1016/j.ceb.2007.04.002.

    Google Scholar 

  • Mason SF. Purine Studies. Part II. The Ultra-violet absorption spectra of some mono- and poly-substituted purines. J Chem Soc. 1954:2071–81.

    Google Scholar 

  • McClelland M. Selection against dam methylation sites in the genomes of DNA of enterobacteriophages. J Mol Evol. 1984;21(4):317–22.

    Article  PubMed  Google Scholar 

  • Meselson M, Yuan R. DNA restriction enzyme from E. coli. Nature. 1968;217(5134):1110–4.

    Article  CAS  PubMed  Google Scholar 

  • Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell. 2012;149(7):1635–46. doi:10.1016/j.cell.2012.05.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mills JB, Hagerman PJ. Origin of the intrinsic rigidity of DNA. Nucleic Acids Res. 2004;32(13):4055–9. doi:10.1093/nar/gkh740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Montero LM, Filipski J, Gil P, Capel J, Martinez-Zapater JM, Salinas J. The distribution of 5-methylcytosine in the nuclear genome of plants. Nucleic Acids Res. 1992;20(12):3207–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murchie AI, Lilley DM. Base methylation and local DNA helix stability. Effect on the kinetics of cruciform extrusion. J Mol Biol. 1989;205(3):593–602.

    Article  CAS  PubMed  Google Scholar 

  • Murray NE. 2001 Fred Griffith review lecture. Immigration control of DNA in bacteria: self versus non-self. Microbiology. 2002;148(Pt 1):3–20. doi:10.1099/00221287-148-1-3.

    Article  CAS  PubMed  Google Scholar 

  • Nikolskaya II, Lopatina NG, Chaplygina NM, Debov SS. The host specificity system in Escherichia coli SK. Mol Cell Biochem. 1976;13(2):79–87.

    Article  CAS  PubMed  Google Scholar 

  • Nikolskaya II, Lopatina NG, Debov SS. On heterogeneity of DNA methylases from Escherichia coli SK cells. Mol Cell Biochem. 1981;35(1):3–10.

    Article  CAS  PubMed  Google Scholar 

  • Niu Y, Zhao X, Wu YS, Li MM, Wang XJ, Yang YG. N6-methyl-adenosine (m6A) in RNA: an old modification with a novel epigenetic function. Genomics Proteomics Bioinformatics. 2013;11(1):8–17. doi:10.1016/j.gpb.2012.12.002.

    Article  CAS  PubMed  Google Scholar 

  • Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99(3):247–57.

    Article  CAS  PubMed  Google Scholar 

  • Parfrey LW, Lahr DJ, Knoll AH, Katz LA. Estimating the timing of early eukaryotic diversification with multigene molecular clocks. Proc Natl Acad Sci U S A. 2011;108(33):13624–9. doi:10.1073/pnas.1110633108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peng S, Padva A, LeBreton PR. Ultraviolet photoelectron studies of biological purines: the valence electronic structure of adenine. Proc Natl Acad Sci U S A. 1976;73(9):2966–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pogolotti Jr AL, Ono A, Subramaniam R, Santi DV. On the mechanism of DNA-adenine methylase. J Biol Chem. 1988;263(16):7461–4.

    CAS  PubMed  Google Scholar 

  • Pomraning KR, Smith KM, Freitag M. Genome-wide high throughput analysis of DNA methylation in eukaryotes. Methods. 2009;47(3):142–50. doi:10.1016/j.ymeth.2008.09.022.

    Article  CAS  PubMed  Google Scholar 

  • Posfai G, Szybalski W. A simple method for locating methylated bases in DNA using class-IIS restriction enzymes. Gene. 1988;74(1):179–81.

    Article  CAS  PubMed  Google Scholar 

  • Pratt K, Hattman S. Nucleosome phasing in Tetrahymena macronuclei. J Protozool. 1983;30(3):592–8.

    Article  CAS  PubMed  Google Scholar 

  • Privat E, Sowers LC. Photochemical deamination and demethylation of 5-methylcytosine. Chem Res Toxicol. 1996;9(4):745–50. doi:10.1021/tx950182o.

    Article  CAS  PubMed  Google Scholar 

  • Proffitt JH, Davie JR, Swinton D, Hattman S. 5-Methylcytosine is not detectable in Saccharomyces cerevisiae DNA. Mol Cell Biol. 1984;4(5):985–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pukkila PJ, Peterson J, Herman G, Modrich P, Meselson M. Effects of high levels of DNA adenine methylation on methyl-directed mismatch repair in Escherichia coli. Genetics. 1983;104(4):571–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Quignard E, Fazakerley GV, Teoule R, Guy A, Guschlbauer W. Consequences of methylation on the amino group of adenine. A proton two-dimensional NMR study of d(GGATATCC) and d(GGm6ATATCC). Eur J Biochem. 1985;152(1):99–105.

    Article  CAS  PubMed  Google Scholar 

  • Rae PM. Hydroxymethyluracil in eukaryote DNA: a natural feature of the pyrrophyta (dinoflagellates). Science (New York, NY). 1976;194(4269):1062–4.

    Article  CAS  Google Scholar 

  • Rae PM, Spear BB. Macronuclear DNA of the hypotrichous ciliate Oxytricha fallax. Proc Natl Acad Sci U S A. 1978;75(10):4992–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Razin A, Razin S. Methylated bases in mycoplasmal DNA. Nucleic Acids Res. 1980;8(6):1383–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reich NO, Mashhoon N. Kinetic mechanism of the EcoRI DNA methyltransferase. Biochemistry. 1991;30(11):2933–9.

    Article  CAS  PubMed  Google Scholar 

  • Robbins-Manke JL, Zdraveski ZZ, Marinus M, Essigmann JM. Analysis of global gene expression and double-strand-break formation in DNA adenine methyltransferase- and mismatch repair-deficient Escherichia coli. J Bacteriol. 2005;187(20):7027–37. doi:10.1128/JB.187.20.7027-7037.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roberts D, Hoopes BC, McClure WR, Kleckner N. IS10 transposition is regulated by DNA adenine methylation. Cell. 1985;43(1):117–30.

    Article  CAS  PubMed  Google Scholar 

  • Rogers JC, Rogers SW. Comparison of the effects of N6-methyldeoxyadenosine and N5-methyldeoxycytosine on transcription from nuclear gene promoters in barley. Plant J. 1995;7(2):221–33.

    Article  CAS  PubMed  Google Scholar 

  • Rogers SD, Rogers ME, Saunders G, Holt G. Isolation of mutants sensitive to 2-aminopurine and alkylating agents and evidence for the role of DNA methylation in Penicillium chrysogenum. Curr Genet. 1986;10(7):557–60.

    Article  CAS  PubMed  Google Scholar 

  • Romanov GA, Vanyushin BF. Methylation of reiterated sequences in mammalian DNAs. Effects of the tissue type, age, malignancy and hormonal induction. Biochim Biophys Acta. 1981;653(2):204–18.

    Article  CAS  PubMed  Google Scholar 

  • Russell DW, Hirata RK. The detection of extremely rare DNA modifications. Methylation in dam- and hsd- Escherichia coli strains. J Biol Chem. 1989;264(18):10787–94.

    CAS  PubMed  Google Scholar 

  • Saparbaev M, Laval J. Excision of hypoxanthine from DNA containing dIMP residues by the Escherichia coli, yeast, rat, and human alkylpurine DNA glycosylases. Proc Natl Acad Sci U S A. 1994;91(13):5873–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sarnacki SH, Castaneda Mdel R, Noto Llana M, Giacomodonato MN, Valvano MA, Cerquetti MC. Dam methylation participates in the regulation of PmrA/PmrB and RcsC/RcsD/RcsB two component regulatory systems in Salmonella enterica serovar Enteritidis. PLoS One. 2013;8(2):e56474. doi:10.1371/journal.pone.0056474.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sater MR, Lamelas A, Wang G, Clark TA, Roltgen K, Mane S, et al. DNA methylation assessed by SMRT sequencing is linked to mutations in Neisseria meningitidis isolates. PLoS One. 2015;10(12):e0144612. doi:10.1371/journal.pone.0144612.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sedgwick B, Bates PA, Paik J, Jacobs SC, Lindahl T. Repair of alkylated DNA: recent advances. DNA Repair (Amst). 2007;6(4):429–42. doi:10.1016/j.dnarep.2006.10.005.

    Article  CAS  Google Scholar 

  • Seisenberger S, Andrews S, Krueger F, Arand J, Walter J, Santos F, et al. The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol Cell. 2012;48(6):849–62. doi:10.1016/j.molcel.2012.11.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shapiro R, Klein RS. The deamination of cytidine and cytosine by acidic buffer solutions. Mutagenic implications. Biochemistry. 1966;5(7):2358–62.

    Article  CAS  PubMed  Google Scholar 

  • Shen L, Song CX, He C, Zhang Y. Mechanism and function of oxidative reversal of DNA and RNA methylation. Annu Rev Biochem. 2014;83:585–614. doi:10.1146/annurev-biochem-060713-035513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Slater S, Wold S, Lu M, Boye E, Skarstad K, Kleckner N. E. coli SeqA protein binds oriC in two different methyl-modulated reactions appropriate to its roles in DNA replication initiation and origin sequestration. Cell. 1995;82(6):927–36.

    Article  CAS  PubMed  Google Scholar 

  • Smith JD, Arber W, Kuhnlein U. Host specificity of DNA produced by Escherichia coli. XIV. The role of nucleotide methylation in in vivo B-specific modification. J Mol Biol. 1972;63(1):1–8.

    Article  CAS  PubMed  Google Scholar 

  • Srivastava R, Gopinathan KP, Ramakrishnan T. Deoxyribonucleic acid methylation in mycobacteria. J Bacteriol. 1981;148(2):716–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stein R, Gruenbaum Y, Pollack Y, Razin A, Cedar H. Clonal inheritance of the pattern of DNA methylation in mouse cells. Proc Natl Acad Sci U S A. 1982;79(1):61–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stephens C, Reisenauer A, Wright R, Shapiro L. A cell cycle-regulated bacterial DNA methyltransferase is essential for viability. Proc Natl Acad Sci U S A. 1996;93(3):1210–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sternglanz H, Bugg CE. Conformation of N6-methyladenine, a base involved in DNA modification: restriction processes. Science (New York, NY). 1973;182(4114):833–4.

    Article  CAS  Google Scholar 

  • Su SS, Modrich P. Escherichia coli mutS-encoded protein binds to mismatched DNA base pairs. Proc Natl Acad Sci U S A. 1986;83(14):5057–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sugimoto K, Takeda S, Hirochika H. Transcriptional activation mediated by binding of a plant GATA-type zinc finger protein AGP1 to the AG-motif (AGATCCAA) of the wound-inducible Myb gene NtMyb2. Plant J. 2003;36(4):550–64.

    Article  CAS  PubMed  Google Scholar 

  • Sun Q, Huang S, Wang X, Zhu Y, Chen Z, Chen D. N(6) -methyladenine functions as a potential epigenetic mark in eukaryotes. Bioessays. 2015;37(11):1155–62. doi:10.1002/bies.201500076.

    Article  CAS  PubMed  Google Scholar 

  • Sundheim O, Talstad VA, Vagbo CB, Slupphaug G, Krokan HE. AlkB demethylases flip out in different ways. DNA Repair (Amst). 2008;7(11):1916–23. doi:10.1016/j.dnarep.2008.07.015.

    Article  CAS  Google Scholar 

  • Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science (New York, NY). 2009;324(5929):930–5. doi:10.1126/science.1170116.

    Article  CAS  Google Scholar 

  • Tawa R, Ueno S, Yamamoto K, Yamamoto Y, Sagisaka K, Katakura R, et al. Methylated cytosine level in human liver DNA does not decline in aging process. Mech Ageing Dev. 1992;62(3):255–61.

    Article  CAS  PubMed  Google Scholar 

  • Theil EC, Zamenhof S. Studies on 6-methylaminopurine (6-methyladenine) in bacterial deoxyribonucleic acid. J Biol Chem. 1963;238:3058–64.

    CAS  PubMed  Google Scholar 

  • Trewick SC, Henshaw TF, Hausinger RP, Lindahl T, Sedgwick B. Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage. Nature. 2002;419(6903):174–8. doi:10.1038/nature00908.

    Article  CAS  PubMed  Google Scholar 

  • Tronche F, Rollier A, Bach I, Weiss MC, Yaniv M. The rat albumin promoter: cooperation with upstream elements is required when binding of APF/HNF1 to the proximal element is partially impaired by mutation or bacterial methylation. Mol Cell Biol. 1989;9(11):4759–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsuchiya H, Matsuda T, Harashima H, Kamiya H. Cytokine induction by a bacterial DNA-specific modified base. Biochem Biophys Res Commun. 2005;326(4):777–81. doi:10.1016/j.bbrc.2004.11.115.

    Article  CAS  PubMed  Google Scholar 

  • Unger G, Venner H. Remarks on minor bases in spermatic desoxyribonucleic acid. Hoppe Seylers Z Physiol Chem. 1966;344(4):280–3.

    Article  CAS  PubMed  Google Scholar 

  • Urbonavicius J, Skouloubris S, Myllykallio H, Grosjean H. Identification of a novel gene encoding a flavin-dependent tRNA:m5U methyltransferase in bacteria--evolutionary implications. Nucleic Acids Res. 2005;33(13):3955–64. doi:10.1093/nar/gki703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Urig S, Gowher H, Hermann A, Beck C, Fatemi M, Humeny A, et al. The Escherichia coli dam DNA methyltransferase modifies DNA in a highly processive reaction. J Mol Biol. 2002;319(5):1085–96. doi:10.1016/S0022-2836(02)00371-6.

    Article  CAS  PubMed  Google Scholar 

  • van den Born E, Omelchenko MV, Bekkelund A, Leihne V, Koonin EV, Dolja VV, et al. Viral AlkB proteins repair RNA damage by oxidative demethylation. Nucleic Acids Res. 2008;36(17):5451–61. doi:10.1093/nar/gkn519.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Van Etten JL, Schuster AM, Girton L, Burbank DE, Swinton D, Hattman S. DNA methylation of viruses infecting a eukaryotic Chlorella-like green alga. Nucleic Acids Res. 1985;13(10):3471–8.

    Article  PubMed  PubMed Central  Google Scholar 

  • Vanyushin BF, Belozersky AN, Kokurina NA, Kadirova DX. 5-methylcytosine and 6-methylamino-purine in bacterial DNA. Nature. 1968;218(5146):1066–7.

    Article  CAS  PubMed  Google Scholar 

  • Vanyushin BF, Tkacheva SG, Belozersky AN. Rare bases in animal DNA. Nature. 1970;225(5236):948–9.

    Article  CAS  PubMed  Google Scholar 

  • von Freiesleben U, Rasmussen KV, Schaechter M. SeqA limits DnaA activity in replication from oriC in Escherichia coli. Mol Microbiol. 1994;14(4):763–72.

    Article  CAS  Google Scholar 

  • Wagner I, Capesius I. Determination of 5-methylcytosine from plant DNA by high-performance liquid chromatography. Biochim Biophys Acta. 1981;654(1):52–6.

    Article  CAS  PubMed  Google Scholar 

  • Wallecha A, Munster V, Correnti J, Chan T, van der Woude M. Dam- and OxyR-dependent phase variation of agn43: essential elements and evidence for a new role of DNA methylation. J Bacteriol. 2002;184(12):3338–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014;505(7481):117–20. doi:10.1038/nature12730.

    Article  PubMed  CAS  Google Scholar 

  • Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, et al. N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell. 2015;161(6):1388–99. doi:10.1016/j.cell.2015.05.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weber M, Davies JJ, Wittig D, Oakeley EJ, Haase M, Lam WL, et al. Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet. 2005;37(8):853–62. doi:10.1038/ng1598.

    Article  CAS  PubMed  Google Scholar 

  • Wei YF, Carter KC, Wang RP, Shell BK. Molecular cloning and functional analysis of a human cDNA encoding an Escherichia coli AlkB homolog, a protein involved in DNA alkylation damage repair. Nucleic Acids Res. 1996;24(5):931–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Willis DB, Granoff A. Frog virus 3 DNA is heavily methylated at CpG sequences. Virology. 1980;107(1):250–7.

    Article  CAS  PubMed  Google Scholar 

  • Wion D, Casadesus J. N6-methyl-adenine: an epigenetic signal for DNA-protein interactions. Nat Rev Microbiol. 2006;4(3):183–92. doi:10.1038/nrmicro1350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wold S, Boye E, Slater S, Kleckner N, Skarstad K. Effects of purified SeqA protein on oriC-dependent DNA replication in vitro. EMBO J. 1998;17(14):4158–65. doi:10.1093/emboj/17.14.4158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu JC, Santi DV. Kinetic and catalytic mechanism of HhaI methyltransferase. J Biol Chem. 1987;262(10):4778–86.

    CAS  PubMed  Google Scholar 

  • Wu TP, Wang T, Seetin MG, Lai Y, Zhu S, Lin K, et al. DNA methylation on N-adenine in mammalian embryonic stem cells. Nature. 2016. doi:10.1038/nature17640.

    Google Scholar 

  • Wyatt GR. Occurrence of 5-methylcytosine in nucleic acids. Nature. 1950;166(4214):237–8.

    Article  CAS  PubMed  Google Scholar 

  • Wyatt GR, Cohen SS. A new pyrimidine base from bacteriophage nucleic acids. Nature. 1952;170(4338):1072–3.

    Article  CAS  PubMed  Google Scholar 

  • Yamaki H, Ohtsubo E, Nagai K, Maeda Y. The oriC unwinding by dam methylation in Escherichia coli. Nucleic Acids Res. 1988;16(11):5067–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang CG, Yi C, Duguid EM, Sullivan CT, Jian X, Rice PA, et al. Crystal structures of DNA/RNA repair enzymes AlkB and ABH2 bound to dsDNA. Nature. 2008;452(7190):961–5. doi:10.1038/nature06889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoder JA, Soman NS, Verdine GL, Bestor TH. DNA (cytosine-5)-methyltransferases in mouse cells and tissues. Studies with a mechanism-based probe. J Mol Biol. 1997;270(3):385–95. doi:10.1006/jmbi.1997.1125.

    Article  CAS  PubMed  Google Scholar 

  • Yue Y, Liu J, He C. RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation. Genes Dev. 2015;29(13):1343–55. doi:10.1101/gad.262766.115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yuki H, Kawasaki H, Imayuki A, Yajima T. Determination of 6-methyladenine in DNA by high-performance liquid chromatography. J Chromatogr. 1979;168(2):489–94.

    Article  CAS  PubMed  Google Scholar 

  • Zaleski P, Wojciechowski M, Piekarowicz A. The role of Dam methylation in phase variation of Haemophilus influenzae genes involved in defence against phage infection. Microbiology. 2005;151(Pt 10):3361–9. doi:10.1099/mic.0.28184-0.

    Article  CAS  PubMed  Google Scholar 

  • Zelinkova E, Paulicek M, Zelinka J. Modification methylase M. Sau3239I from Streptomyces aureofaciens 3239. FEBS Lett. 1990;271(1–2):147–8.

    Article  CAS  PubMed  Google Scholar 

  • Zhang G, Huang H, Liu D, Cheng Y, Liu X, Zhang W, et al. N(6)-methyladenine DNA modification in Drosophila. Cell. 2015;161(4):893–906. doi:10.1016/j.cell.2015.04.018.

    Article  CAS  PubMed  Google Scholar 

  • Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2013;49(1):18–29. doi:10.1016/j.molcel.2012.10.015.

    Article  CAS  PubMed  Google Scholar 

  • Zhou J, Wan 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):591–4. doi:10.1038/nature15377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank S. Burger, N. O’Brown, and E. Pollina for critical reading of the manuscript. We thank C. He for helpful discussions. The work from the Greer laboratory is supported by a grant from the NIH (AG043550). Z.K.O. is supported by 5T32HD7466-19.

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O’Brown, Z.K., Greer, E.L. (2016). N6-Methyladenine: A Conserved and Dynamic DNA Mark. In: Jeltsch, A., Jurkowska, R. (eds) DNA Methyltransferases - Role and Function. Advances in Experimental Medicine and Biology, vol 945. Springer, Cham. https://doi.org/10.1007/978-3-319-43624-1_10

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