Abstract
Chromatin, consisting of deoxyribonucleic acid (DNA) wrapped around histone proteins, facilitates DNA compaction and allows identical DNA code to confer many different cellular phenotypes. This biological versatility is accomplished in large part by post-translational modifications to histones and chemical modifications to DNA. These modifications direct the cellular machinery to expand or compact specific chromatin regions and mark certain 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., Prog Mol Biol Transl Sci. 101:25–104, 2011), this chapter will focus on methylation of the 6th position on adenines (6mA). 6mA is a prevalent modification in unicellular organisms and until recently was thought to be restricted to them. A flurry of conflicting studies have proposed that 6mA either does not exist, is present at low levels, or is present at relatively high levels and regulates complex processes in different multicellular eukaryotes. 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 proteins that have been reported to bind and regulate 6mA and examine the known and potential functions of this modification in eukaryotes. Finally, we will close with a discussion of the ongoing debate about whether 6mA exists as a directed DNA modification in multicellular eukaryotes.
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References
Aas PA, Otterlei M, Falnes PO, Vagbo CB, Skorpen F, Akbari M et al (2003) Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA. Nature. 421(6925):859–863. https://doi.org/10.1038/nature01363
Achwal CW, Iyer CA, Chandra HS (1983) Immunochemical evidence for the presence of 5mC, 6mA and 7mG in human, Drosophila and mealybug DNA. FEBS Lett. 158(2):353–358
Adams RL, McKay EL, Craig LM, Burdon RH (1979) Methylation of mosquito DNA. Biochim Biophys Acta. 563(1):72–81
Allamane S, Jourdes P, Ratel D, Vicat JM, Dupre I, Laine M et al (2000) Bacterial DNA methylation and gene transfer efficiency. Biochem Biophys Res Commun. 276(3):1261–1264. https://doi.org/10.1006/bbrc.2000.3603
Allan BW, Beechem JM, Lindstrom WM, Reich NO (1998) Direct real time observation of base flipping by the EcoRI DNA methyltransferase. J Biol Chem 273(4):2368–2373
Ammermann D, Steinbruck G, Baur R, Wohlert H (1981) Methylated bases in the DNA of the ciliate Stylonychia mytilus. Eur J Cell Biol. 24(1):154–156
Aravind L, Zhang D, Iyer LM (2015) 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 3(12):289
Babinger P, Kobl I, Mages W, Schmitt R (2001) A link between DNA methylation and epigenetic silencing in transgenic Volvox carteri. Nucleic Acids Res. 29(6):1261–1271
Bakker A, Smith DW (1989) Methylation of GATC sites is required for precise timing between rounds of DNA replication in Escherichia coli. J Bacteriol. 171(10):5738–5742
Bashtrykov P, Jeltsch A (2018) DNA Methylation Analysis by Bisulfite Conversion Coupled to Double Multiplexed Amplicon-Based Next-Generation Sequencing (NGS). Methods Mol Biol. 1767:367–382. https://doi.org/10.1007/978-1-4939-7774-1_20
Batista PJ, Molinie B, Wang J, Qu K, Zhang J, Li L et al (2014) m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell. 15(6):707–719. https://doi.org/10.1016/j.stem.2014.09.019
Bayley H (2015) Nanopore sequencing: from imagination to reality. Clin Chem. 61(1):25–31. https://doi.org/10.1373/clinchem.2014.223016
Beh LY, Debelouchina GT, Clay DM, Thompson RE, Lindblad KA, Hutton ER et al (2019) Identification of a DNA N6-adenine methyltransferase complex and its impact on chromatin organization. Cell. 177(7):1781–1796. e25. https://doi.org/10.1016/j.cell.2019.04.028
Berdis AJ, Lee I, Coward JK, Stephens C, Wright R, Shapiro L et al (1998) A cell cycle-regulated adenine DNA methyltransferase from Caulobacter crescentus processively methylates GANTC sites on hemimethylated DNA. Proc Nat Acad Sci U S A 95(6):2874–2879
Bestor TH (2000) The DNA methyltransferases of mammals. Hum Mol Genet. 9(16):2395–2402
Bestor T, Laudano A, Mattaliano R, Ingram V (1988) 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. 203(4):971–983
Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16(1):6–21. https://doi.org/10.1101/gad.947102
Bird AP, Southern EM (1978) Use of restriction enzymes to study eukaryotic DNA methylation: I. The methylation pattern in ribosomal DNA from Xenopus laevis. J Mol Biol. 118(1):27–47
Bodi Z, Zhong S, Mehra S, Song J, Graham N, Li H et al (2012) Adenosine methylation in arabidopsis mRNA is associated with the 3′ end and reduced levels cause developmental defects. Front Plant Sci. 3:48. https://doi.org/10.3389/fpls.2012.00048
Boulias K, Greer EL (2021) Detection of DNA Methylation in Genomic DNA by UHPLC-MS/MS. Methods Mol Biol. 2198:79–90. https://doi.org/10.1007/978-1-0716-0876-0_7
Boye E, Lobner-Olesen A (1990) The role of dam methyltransferase in the control of DNA replication in E. coli. Cell. 62(5):981–989
Brendler T, Abeles A, Austin S (1995) 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. The EMBO journal. 14(16):4083–4089
Bromberg S, Pratt K, Hattman S (1982) Sequence specificity of DNA adenine methylase in the protozoan Tetrahymena thermophila. J Bacteriol. 150(2):993–996
Campbell JL, Kleckner N (1990) E. coli oriC and the dnaA gene promoter are sequestered from dam methyltransferase following the passage of the chromosomal replication fork. Cell. 62(5):967–979
Capowski EE, Wells JM, Harrison GS, Karrer KM (1989) Molecular analysis of N6-methyladenine patterns in Tetrahymena thermophila nuclear DNA. Mol Cell Biol. 9(6):2598–2605
Capuano F, Mulleder M, Kok R, Blom HJ, Ralser M (2014) Cytosine DNA methylation is found in Drosophila melanogaster but absent in Saccharomyces cerevisiae, Schizosaccharomyces pombe, and other yeast species. Anal Chem. 86(8):3697–3702. https://doi.org/10.1021/ac500447w
Casadesus J, Low D (2006) Epigenetic gene regulation in the bacterial world. Microbiol Mol Biol Rev. 70(3):830–856. https://doi.org/10.1128/MMBR.00016-06
Charles MP, Ravanat JL, Adamski D, D‘Orazi G, Cadet J, Favier A et al (2004) N(6)-Methyldeoxyadenosine, a nucleoside commonly found in prokaryotes, induces C2C12 myogenic differentiation. Biochem Biophys Res Commun. 314(2):476–482
Chen Z, Zhang Y (2020) Role of mammalian DNA methyltransferases in development. Annu Rev Biochem. 89:135–158. https://doi.org/10.1146/annurev-biochem-103019-102815
Chen K, Luo GZ, He C (2015) High-resolution mapping of N(6)-methyladenosine in transcriptome and genome using a photo-crosslinking-assisted strategy. Methods Enzymol. 560:161–185. https://doi.org/10.1016/bs.mie.2015.03.012
Chen H, Gu L, Orellana EA, Wang Y, Guo J, Liu Q et al (2020) METTL4 is an snRNA m(6)Am methyltransferase that regulates RNA splicing. Cell Res. 30(6):544–547. https://doi.org/10.1038/s41422-019-0270-4
Cheng SC, Herman G, Modrich P (1985) Extent of equilibrium perturbation of the DNA helix upon enzymatic methylation of adenine residues. J Biol Chem 260(1):191–194
Chiang PK, Gordon RK, Tal J, Zeng GC, Doctor BP, Pardhasaradhi K et al (1996) S-Adenosylmethionine and methylation. FASEB J. 10(4):471–480
Clancy MJ, Shambaugh ME, Timpte CS, Bokar JA (2002) 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. 30(20):4509–4518
Collier J, McAdams HH, Shapiro L (2007) A DNA methylation ratchet governs progression through a bacterial cell cycle. Proc Nat Acad Sci U S A 104(43):17111–17116. https://doi.org/10.1073/pnas.0708112104
Collins M, Myers RM (1987) Alterations in DNA helix stability due to base modifications can be evaluated using denaturing gradient gel electrophoresis. J Mol Biol. 198(4):737–744
Cummings DJ, Tait A, Goddard JM (1974) Methylated bases in DNA from Paramecium aurelia. Biochim Biophys Acta. 374(1):1–11
Degnen ST, Morris NR (1973) Deoxyribonucleic acid methylation and development in Caulobacter bacteroides. J Bacteriol. 116(1):48–53
Delk AS, Rabinowitz JC (1975) Biosynthesis of ribosylthymine in the transfer RNA of Streptococcus faecalis: a folate-dependent methylation not involving S-adenosylmethionine. Proc Nat Acad Sci U S A 72(2):528–530
Delk AS, Romeo JM, Nagle DP Jr, Rabinowitz JC (1976) Biosynthesis of ribothymidine in the transfer RNA of Streptococcus faecalis and Bacillus subtilis. A methylation of RNA involving 5,10-methylenetetrahydrofolate. J Biol Chem 251(23):7649–7656
Deng X, Chen K, Luo GZ, Weng X, Ji Q, Zhou T et al (2015) Widespread occurrence of N6-methyladenosine in bacterial mRNA. Nucleic Acids Res. 43(13):6557–6567. https://doi.org/10.1093/nar/gkv596
Diekmann S (1987) DNA methylation can enhance or induce DNA curvature. EMBO J 6(13):4213–4217
Dohno C, Shibata T, Nakatani K (2010) Discrimination of N6-methyl adenine in a specific DNA sequence. Chem Commun (Camb). 46(30):5530–5532. https://doi.org/10.1039/c0cc00172d
Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S et al (2012) Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 485(7397):201–206. https://doi.org/10.1038/nature11112
Douvlataniotis K, Bensberg M, Lentini A, Gylemo B, Nestor CE (2020) No evidence for DNA N (6)-methyladenine in mammals. Sci Adv 6(12):eaay3335. https://doi.org/10.1126/sciadv.aay3335
Drozdz M, Piekarowicz A, Bujnicki JM, Radlinska M (2012) Novel non-specific DNA adenine methyltransferases. Nucleic Acids Res. 40(5):2119–2130. https://doi.org/10.1093/nar/gkr1039
Du J, Zhong X, Bernatavichute YV, Stroud H, Feng S, Caro E et al (2012) Dual binding of chromomethylase domains to H3K9me2-containing nucleosomes directs DNA methylation in plants. Cell. 151(1):167–180. https://doi.org/10.1016/j.cell.2012.07.034
Du K, Zhang X, Zou Z, Li B, Gu S, Zhang S et al (2019) Epigenetically modified N(6)-methyladenine inhibits DNA replication by human DNA polymerase eta. DNA Repair (Amst) 78:81–90. https://doi.org/10.1016/j.dnarep.2019.03.015
Duncan T, Trewick SC, Koivisto P, Bates PA, Lindahl T, Sedgwick B (2002) Reversal of DNA alkylation damage by two human dioxygenases. Proc Nat Acad Sci U S A 99(26):16660–16665. https://doi.org/10.1073/pnas.262589799
Dunn DB, Smith JD (1955) Occurrence of a new base in the deoxyribonucleic acid of a strain of Bacterium coli. Nature. 175(4451):336–337
Dunn DB, Smith JD (1958) The occurrence of 6-methylaminopurine in deoxyribonucleic acids. Biochem J. 68(4):627–636
Ehrlich M, Gama-Sosa MA, Huang LH, Midgett RM, Kuo KC, McCune RA et al (1982) Amount and distribution of 5-methylcytosine in human DNA from different types of tissues of cells. Nucleic Acids Res. 10(8):2709–2721
Ehrlich M, Gama-Sosa MA, Carreira LH, Ljungdahl LG, Kuo KC, Gehrke CW (1985) DNA methylation in thermophilic bacteria: N4-methylcytosine, 5-methylcytosine, and N6-methyladenine. Nucleic Acids Res. 13(4):1399–1412
Ehrlich M, Wilson GG, Kuo KC, Gehrke CW (1987) N4-methylcytosine as a minor base in bacterial DNA. J Bacteriol. 169(3):939–943
Engel JD, von Hippel PH (1978a) D(M6ATP) as a probe of the fidelity of base incorporation into polynucleotides by Escherichia coli DNA polymerase I. J Biol Chem 253(3):935–939
Engel JD, von Hippel PH (1978b) Effects of methylation on the stability of nucleic acid conformations. Studies at the polymer level. J Biol Chem 253(3):927–934
Falnes PO, Johansen RF, Seeberg E (2002) AlkB-mediated oxidative demethylation reverses DNA damage in Escherichia coli. Nature. 419(6903):178–182. https://doi.org/10.1038/nature01048
Fazakerley GV, Guy A, Teoule R, Quignard E, Guschlbauer W (1985) A proton 2D-NMR study of an oligodeoxyribonucleotide containing N6-methyladenine:d(GGm6ATATCC). Biochimie. 67(7-8):819–822
Fazakerley GV, Quignard E, Teoule R, Guy A, Guschlbauer W (1987) 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. 167(3):397–404
Fazakerley GV, Gabarro-Arpa J, Lebret M, Guy A, Guschlbauer W (1989) The GTm6AC sequence is overwound and bent. Nucleic Acids Res. 17(7):2541–2556
Fedeles BI, Singh V, Delaney JC, Li D, Essigmann JM (2015) The AlkB family of Fe(II)/alpha-Ketoglutarate-dependent Dioxygenases: repairing nucleic acid alkylation damage and beyond. J Biol Chem 290(34):20734–20742. https://doi.org/10.1074/jbc.R115.656462
Fernandes SB, Grova N, Roth S, Duca RC, Godderis L, Guebels P et al (2021) N(6)-Methyladenine in Eukaryotic DNA: tissue distribution, early embryo development, and neuronal toxicity. Front Genet. 12:657171. https://doi.org/10.3389/fgene.2021.657171
Fleissner E, Borek E (1962) A new enzyme of RNA synthesis: RNA methylase. Proc Nat Acad Sci U S A 48:1199–1203
Flusberg BA, Webster DR, Lee JH, Travers KJ, Olivares EC, Clark TA et al (2010) Direct detection of DNA methylation during single-molecule, real-time sequencing. Nat Methods. 7(6):461–465. https://doi.org/10.1038/nmeth.1459
Frye M, Harada BT, Behm M, He C (2018) RNA modifications modulate gene expression during development. Science (New York, NY) 361(6409):1346–1349. https://doi.org/10.1126/science.aau1646
Fu Y, Jia G, Pang X, Wang RN, Wang X, Li CJ et al (2013) FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA. Nat Commun. 4:1798. https://doi.org/10.1038/ncomms2822
Fu Y, Luo GZ, Chen K, Deng X, Yu M, Han D et al (2015) N(6)-methyldeoxyadenosine marks active transcription start sites in chlamydomonas. Cell. 161(4):879–892. https://doi.org/10.1016/j.cell.2015.04.010
Fujikawa N, Kurumizaka H, Nureki O, Tanaka Y, Yamazoe M, Hiraga S et al (2004) Structural and biochemical analyses of hemimethylated DNA binding by the SeqA protein. Nucleic Acids Res. 32(1):82–92. https://doi.org/10.1093/nar/gkh173
Fukui K (2010) DNA mismatch repair in eukaryotes and bacteria. J Nucleic Acids. 2010. https://doi.org/10.4061/2010/260512
Gama-Sosa MA, Midgett RM, Slagel VA, Githens S, Kuo KC, Gehrke CW et al (1983) Tissue-specific differences in DNA methylation in various mammals. Biochim Biophys Acta. 740(2):212–219
Geier GE, Modrich P (1979) Recognition sequence of the dam methylase of Escherichia coli K12 and mode of cleavage of Dpn I endonuclease. J Biol Chem 254(4):1408–1413
Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS et al (2007) The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science (New York, NY) 318(5855):1469–1472. https://doi.org/10.1126/science.1151710
Glickman BW (1979) Spontaneous mutagenesis in Escherichia coli strains lacking 6-methyladenine residues in their DNA: an altered mutational spectrum in dam- mutants. Mutat Res. 61(2):153–162
Glickman B, van den Elsen P, Radman M (1978) Induced mutagenesis in dam- mutants of Escherichia coli: a role for 6-methyladenine residues in mutation avoidance. Mol Gen Genet. 163(3):307–312
Goedecke K, Pignot M, Goody RS, Scheidig AJ, Weinhold E (2001) Structure of the N6-adenine DNA methyltransferase M.TaqI in complex with DNA and a cofactor analog. Nat Struct Biol. 8(2):121–125. https://doi.org/10.1038/84104
Goh YT, Koh CWQ, Sim DY, Roca X, Goh WSS (2020) METTL4 catalyzes m6Am methylation in U2 snRNA to regulate pre-mRNA splicing. Nucleic Acids Res. 48(16):9250–9261. https://doi.org/10.1093/nar/gkaa684
Gold M, Hurwitz J (1964) 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 239:3858–3865
Gold M, Hurwitz J, Anders M (1963) The enzymatic methylation of RNA and DNA. Biochem Biophys Res Commun. 11:107–114
Gommers-Ampt JH, Borst P (1995) Hypermodified bases in DNA. FASEB J. 9(11):1034–1042
Gommers-Ampt JH, Van Leeuwen F, de Beer AL, Vliegenthart JF, Dizdaroglu M, Kowalak JA et al (1993) beta-D-glucosyl-hydroxymethyluracil: a novel modified base present in the DNA of the parasitic protozoan T. brucei. Cell. 75(6):1129–1136
Gorovsky MA, Hattman S, Pleger GL (1973) (6N)methyl adenine in the nuclear DNA of a eucaryote, Tetrahymena pyriformis. J Cell Biol. 56(3):697–701
Graham MW, Larkin PJ (1995) Adenine methylation at dam sites increases transient gene expression in plant cells. Transgenic Res. 4(5):324–331
Greer EL, Beese-Sims SE, Brookes E, Spadafora R, Zhu Y, Rothbart SB et al (2014) A histone methylation network regulates transgenerational epigenetic memory in C. elegans. Cell Reports. 7(1):113–126. https://doi.org/10.1016/j.celrep.2014.02.044
Greer EL, Blanco MA, Gu L, Sendinc E, Liu J, Aristizabal-Corrales D et al (2015) DNA Methylation on N(6)-Adenine in C. elegans. Cell. 161(4):868–878. https://doi.org/10.1016/j.cell.2015.04.005
Greer EL, Becker B, Latza C, Antebi A, Shi Y (2016) Mutation of C. elegans demethylase spr-5 extends transgenerational longevity. Cell Res. 26(2):229–238. https://doi.org/10.1038/cr.2015.148
Grosjean H (2009) Nucleic acids are not boring long polymers of only four types of nucleotides: A guided tour. In: Grosjean H (ed) DNA and RNA modi cation Enzymes: Structure, mechanism, function and evolution. CRC Press, pp 1–18
Gu L, Wang L, Chen H, Hong J, Shen Z, Dhall A et al (2020) CG14906 (mettl4) mediates m(6)A methylation of U2 snRNA in Drosophila. Cell Discov. 6:44. https://doi.org/10.1038/s41421-020-0178-7
Guarne A, Zhao Q, Ghirlando R, Yang W (2002) Insights into negative modulation of E. coli replication initiation from the structure of SeqA-hemimethylated DNA complex. Nat Struct Biol. 9(11):839–843. https://doi.org/10.1038/nsb857
Haag S, Sloan KE, Ranjan N, Warda AS, Kretschmer J, Blessing C et al (2016) NSUN3 and ABH1 modify the wobble position of mt-tRNAMet to expand codon recognition in mitochondrial translation. EMBO J 35(19):2104–2119. https://doi.org/10.15252/embj.201694885
Hagerman KR, Hagerman PJ (1996) Helix rigidity of DNA: the meroduplex as an experimental paradigm. J Mol Biol. 260(2):207–223. https://doi.org/10.1006/jmbi.1996.0393
Hao Z, Wu T, Cui X, Zhu P, Tan C, Dou X et al (2020) N(6)-deoxyadenosine methylation in mammalian mitochondrial DNA. Mol Cell 78(3):382–395. e8. https://doi.org/10.1016/j.molcel.2020.02.018
Hassel M, Cornelius MG, Vom Brocke J, Schmeiser HH (2010) Total nucleotide analysis of Hydra DNA and RNA by MEKC with LIF detection and 32P-postlabeling. Electrophoresis. 31(2):299–302. https://doi.org/10.1002/elps.200900458
Hattman S, Kenny C, Berger L, Pratt K (1978) Comparative study of DNA methylation in three unicellular eucaryotes. J Bacteriol. 135(3):1156–1157
He PC, He C (2021) m(6) A RNA methylation: from mechanisms to therapeutic potential. EMBO J 40(3):e105977. https://doi.org/10.15252/embj.2020105977
He S, Zhang G, Wang J, Gao Y, Sun R, Cao Z et al (2019) 6mA-DNA-binding factor Jumu controls maternal-to-zygotic transition upstream of Zelda. Nat Commun. 10(1):2219. https://doi.org/10.1038/s41467-019-10202-3
Heindell HC, Liu A, Paddock GV, Studnicka GM, Salser WA (1978) The primary sequence of rabbit alpha-globin mRNA. Cell. 15(1):43–54
Hongay CF, Orr-Weaver TL (2011) Drosophila Inducer of MEiosis 4 (IME4) is required for Notch signaling during oogenesis. Proc Nat Acad Sci U S A 108(36):14855–14860. https://doi.org/10.1073/pnas.1111577108
Horton JR, Liebert K, Hattman S, Jeltsch A, Cheng X (2005) Transition from nonspecific to specific DNA interactions along the substrate-recognition pathway of dam methyltransferase. Cell. 121(3):349–361. https://doi.org/10.1016/j.cell.2005.02.021
Horton JR, Liebert K, Bekes M, Jeltsch A, Cheng X (2006) Structure and substrate recognition of the Escherichia coli DNA adenine methyltransferase. J Mol Biol. 358(2):559–570. https://doi.org/10.1016/j.jmb.2006.02.028
Hotchkiss RD (1948) The quantitative separation of purines, pyrimidines, and nucleosides by paper chromatography. J Biol Chem 175(1):315–332
Huang W, Xiong J, Yang Y, Liu SM, Yuan BF, Feng YQ (2015) Determination of DNA adenine methylation in genomes of mammals and plants by liquid chromatography/mass spectrometry. R Soc Chem Adv 5:64046–64054
Ito S, D‘Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y (2010) Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 466(7310):1129–1133. https://doi.org/10.1038/nature09303
Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA et al (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science (New York, NY) 333(6047):1300–1303. https://doi.org/10.1126/science.1210597
Iyer LM, Abhiman S, Aravind L (2011) Natural history of eukaryotic DNA methylation systems. Prog Mol Biol Transl Sci. 101:25–104. https://doi.org/10.1016/B978-0-12-387685-0.00002-0
Jabbari K, Caccio S, Pais de Barros JP, Desgres J, Bernardi G (1997) Evolutionary changes in CpG and methylation levels in the genome of vertebrates. Gene. 205(1-2):109–118
Jackson JP, Lindroth AM, Cao X, Jacobsen SE (2002) Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase. Nature. 416(6880):556–560. https://doi.org/10.1038/nature731
Janulaitis A, Klimasauskas S, Petrusyte M, Butkus V (1983) Cytosine modification in DNA by BcnI methylase yields N4-methylcytosine. FEBS Lett. 161(1):131–134
Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y et al (2011) N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 7(12):885–887. https://doi.org/10.1038/nchembio.687
Johnson TB, Coghill RD (1925) The discovery of 5-methyl-cytosine in tuberculinic acid, the nucleic acid of the Tubercle bacillus. J Am Chem Soc 47:2838–2844
Johnson LM, Bostick M, Zhang X, Kraft E, Henderson I, Callis J et al (2007) The SRA methyl-cytosine-binding domain links DNA and histone methylation. Current biology : CB. 17(4):379–384. https://doi.org/10.1016/j.cub.2007.01.009
Jones PA (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet. 13(7):484–492. https://doi.org/10.1038/nrg3230
Kakutani T, Munakata K, Richards EJ, Hirochika H (1999) Meiotically and mitotically stable inheritance of DNA hypomethylation induced by ddm1 mutation of Arabidopsis thaliana. Genetics. 151(2):831–838
Kamat SS, Fan H, Sauder JM, Burley SK, Shoichet BK, Sali A et al (2011) Enzymatic deamination of the epigenetic base N-6-methyladenine. J Am Chem Soc. 133(7):2080–2083. https://doi.org/10.1021/ja110157u
Karrer KM, VanNuland TA (2002) Methylation of adenine in the nuclear DNA of Tetrahymena is internucleosomal and independent of histone H1. Nucleic Acids Res. 30(6):1364–1370
Katz DJ, Edwards TM, Reinke V, Kelly WG (2009) A C. elegans LSD1 demethylase contributes to germline immortality by reprogramming epigenetic memory. Cell. 137(2):308–320
Koh CWQ, Goh YT, Toh JDW, Neo SP, Ng SB, Gunaratne J et al (2018) Single-nucleotide-resolution sequencing of human N6-methyldeoxyadenosine reveals strand-asymmetric clusters associated with SSBP1 on the mitochondrial genome. Nucleic Acids Res. 46(22):11659–11670. https://doi.org/10.1093/nar/gky1104
Kong Y, Cao L, Deikus G, Fan Y, Mead EA, Lai W et al (2022) Critical assessment of DNA adenine methylation in eukaryotes using quantitative deconvolution. Science (New York, NY.
Kornberg A, Zimmerman SB, Kornberg SR, Josse J (1959) Enzymatic synthesis of deoxyribonucleic acid. Influence of bacteriophage T2 on the synthetic pathway in host cells. Proc Nat Acad Sci U S A 45(6):772–785
Kornberg SR, Zimmerman SB, Kornberg A (1961) Glucosylation of deoxyribonucleic acid by enzymes from bacteriophage-infected Escherichia coli. J Biol Chem 236:1487–1493
Kozdon JB, Melfi MD, Luong K, Clark TA, Boitano M, Wang S et al (2013) Global methylation state at base-pair resolution of the Caulobacter genome throughout the cell cycle. Proc Nat Acad Sci U S A 110(48):E4658–E4667. https://doi.org/10.1073/pnas.1319315110
Koziol MJ, Bradshaw CR, Allen GE, Costa AS, Frezza C, Gurdon JB (2016) Identification of methylated deoxyadenosines in vertebrates reveals diversity in DNA modifications. Nat Struct Mol Biol 23(1):24–30. https://doi.org/10.1038/nsmb.3145
Krais AM, Cornelius MG, Schmeiser HH (2010) Genomic N(6)-methyladenine determination by MEKC with LIF. Electrophoresis. 31(21):3548–3551. https://doi.org/10.1002/elps.201000357
Kweon SM, Chen Y, Moon E, Kvederaviciute K, Klimasauskas S, Feldman DE (2019) An Adversarial DNA N(6)-Methyladenine-sensor network preserves polycomb silencing. Mol Cell. https://doi.org/10.1016/j.molcel.2019.03.018
Lahue RS, Su SS, Modrich P (1987) Requirement for d(GATC) sequences in Escherichia coli mutHLS mismatch correction. Proc Nat Acad Sci U S A 84(6):1482–1486
Lentini A, Lagerwall C, Vikingsson S, Mjoseng HK, Douvlataniotis K, Vogt H et al (2018) A reassessment of DNA-immunoprecipitation-based genomic profiling. Nat Methods. 15(7):499–504. https://doi.org/10.1038/s41592-018-0038-7
Letunic I, Bork P (2011) Interactive Tree Of Life v2: online annotation and display of phylogenetic trees made easy. Nucleic Acids Res 39(Web Server issue):W475-8. https://doi.org/10.1093/nar/gkr201
Li X, Zhao Q, Wei W, Lin Q, Magnan C, Emami MR et al (2019) The DNA modification N6-methyl-2‘-deoxyadenosine (m6dA) drives activity-induced gene expression and is required for fear extinction. Nat Neurosci. 22(4):534–544. https://doi.org/10.1038/s41593-019-0339-x
Li Z, Zhao S, Nelakanti RV, Lin K, Wu TP, Alderman MH 3rd et al (2020) N(6)-methyladenine in DNA antagonizes SATB1 in early development. Nature. 583(7817):625–630. https://doi.org/10.1038/s41586-020-2500-9
Liang Z, Shen L, Cui X, Bao S, Geng Y, Yu G et al (2018) DNA N(6)-Adenine Methylation in Arabidopsis thaliana. Dev Cell. 45(3):406–416. e3. https://doi.org/10.1016/j.devcel.2018.03.012
Lichtsteiner S, Schibler U (1989) A glycosylated liver-specific transcription factor stimulates transcription of the albumin gene. Cell. 57(7):1179–1187
Lindahl T, Nyberg B (1974) Heat-induced deamination of cytosine residues in deoxyribonucleic acid. Biochemistry. 13(16):3405–3410
Linn S, Arber W (1968) Host specificity of DNA produced by Escherichia coli, X. In vitro restriction of phage fd replicative form. Proc Nat Acad Sci U S A 59(4):1300–1306
Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L et al (2014) A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 10(2):93–95. https://doi.org/10.1038/nchembio.1432
Liu F, Clark W, Luo G, Wang X, Fu Y, Wei J et al (2016a) ALKBH1-Mediated tRNA Demethylation Regulates Translation. Cell. 167(3):816–828. e16. https://doi.org/10.1016/j.cell.2016.09.038
Liu J, Zhu Y, Luo GZ, Wang X, Yue Y, Wang X et al (2016b) Abundant DNA 6mA methylation during early embryogenesis of zebrafish and pig. Nat Commun. 7:13052. https://doi.org/10.1038/ncomms13052
Liu B, Liu X, Lai W, Wang H (2017) Metabolically Generated Stable Isotope-Labeled Deoxynucleoside Code for Tracing DNA N(6)-Methyladenine in Human Cells. Anal Chem. 89(11):6202–6209. https://doi.org/10.1021/acs.analchem.7b01152
Liu X, Lai W, Li Y, Chen S, Liu B, Zhang N et al (2021) N(6)-methyladenine is incorporated into mammalian genome by DNA polymerase. Cell Res. 31(1):94–97. https://doi.org/10.1038/s41422-020-0317-6
Lizarraga A, O‘Brown ZK, Boulias K, Roach L, Greer EL, Johnson PJ et al (2020) Adenine DNA methylation, 3D genome organization, and gene expression in the parasite Trichomonas vaginalis. Proc Nat Acad Sci U S A 117(23):13033–13043. https://doi.org/10.1073/pnas.1917286117
Low DA, Weyand NJ, Mahan MJ (2001) Roles of DNA adenine methylation in regulating bacterial gene expression and virulence. Infect Immun. 69(12):7197–7204. https://doi.org/10.1128/IAI.69.12.7197-7204.2001
Lu M, Campbell JL, Boye E, Kleckner N (1994) SeqA: a negative modulator of replication initiation in E. coli. Cell. 77(3):413–426
Luo GZ, Blanco MA, Greer EL, He C, Shi Y (2015) DNA N-methyladenine: a new epigenetic mark in eukaryotes? Nat Rev 16(12):705–710. https://doi.org/10.1038/nrm4076
Luria SE, Human ML (1952) A nonhereditary, host-induced variation of bacterial viruses. J Bacteriol. 64(4):557–569
Lyko F, Ramsahoye BH, Jaenisch R (2000) DNA methylation in Drosophila melanogaster. Nature. 408(6812):538–540. https://doi.org/10.1038/35046205
Ma C, Niu R, Huang T, Shao LW, Peng Y, Ding W et al (2019) N6-methyldeoxyadenine is a transgenerational epigenetic signal for mitochondrial stress adaptation. Nat Cell Biol. 21(3):319–327. https://doi.org/10.1038/s41556-018-0238-5
Macon JB, Wolfenden R (1968) 1-Methyladenosine. Dimroth rearrangement and reversible reduction. Biochemistry. 7(10):3453–3458
Mahdavi-Amiri Y, Chung Kim Chung K, Hili R (2020) Single-nucleotide resolution of N (6)-adenine methylation sites in DNA and RNA by nitrite sequencing. Chem Sci. 12(2):606–612. https://doi.org/10.1039/d0sc03509b
Malagnac F, Bartee L, Bender J (2002) An Arabidopsis SET domain protein required for maintenance but not establishment of DNA methylation. EMBO J 21(24):6842–6852
Malygin EG, Lindstrom WM Jr, Schlagman SL, Hattman S, Reich NO (2000) Pre-steady state kinetics of bacteriophage T4 dam DNA-[N(6)-adenine] methyltransferase: interaction with native (GATC) or modified sites. Nucleic Acids Res. 28(21):4207–4211
Marinus MG (1976) Adenine methylation of Okazaki fragments in Escherichia coli. J Bacteriol. 128(3):853–854
Marinus MG, Lobner-Olesen A (2014) DNA methylation. Ecosal Plus 6(1). https://doi.org/10.1128/ecosalplus.ESP-0003-2013
Marinus MG, Morris NR (1973) Isolation of deoxyribonucleic acid methylase mutants of Escherichia coli K-12. J Bacteriol. 114(3):1143–1150
Marinus MG, Morris NR (1974) Biological function for 6-methyladenine residues in the DNA of Escherichia coli K12. J Mol Biol. 85(2):309–322
Mason SF (1954) Purine Studies. Part II. The Ultra-violet absorption spectra of some mono- and poly-substituted purines. J Chem Soc:2071–2081
McClelland M (1984) Selection against dam methylation sites in the genomes of DNA of enterobacteriophages. J Mol Evol. 21(4):317–322
McIntyre ABR, Alexander N, Grigorev K, Bezdan D, Sichtig H, Chiu CY et al (2019) Single-molecule sequencing detection of N6-methyladenine in microbial reference materials. Nat Commun. 10(1):579. https://doi.org/10.1038/s41467-019-08289-9
Meselson M, Yuan R (1968) DNA restriction enzyme from E. coli. Nature. 217(5134):1110–1114
Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR (2012) Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell. 149(7):1635–1646. https://doi.org/10.1016/j.cell.2012.05.003
Mills JB, Hagerman PJ (2004) Origin of the intrinsic rigidity of DNA. Nucleic Acids Res. 32(13):4055–4059. https://doi.org/10.1093/nar/gkh740
Mondo SJ, Dannebaum RO, Kuo RC, Louie KB, Bewick AJ, LaButti K et al (2017) Widespread adenine N6-methylation of active genes in fungi. Nat Genet 49(6):964–968. https://doi.org/10.1038/ng.3859
Montero LM, Filipski J, Gil P, Capel J, Martinez-Zapater JM, Salinas J (1992) The distribution of 5-methylcytosine in the nuclear genome of plants. Nucleic Acids Res. 20(12):3207–3210
Murchie AI, Lilley DM (1989) Base methylation and local DNA helix stability. Effect on the kinetics of cruciform extrusion. J Mol Biol. 205(3):593–602
Murray NE (2002) 2001 Fred Griffith review lecture. Immigration control of DNA in bacteria: self versus non-self. Microbiology. 148(Pt 1):3–20. https://doi.org/10.1099/00221287-148-1-3
Musheev MU, Baumgartner A, Krebs L, Niehrs C (2020) The origin of genomic N(6)-methyl-deoxyadenosine in mammalian cells. Nat Chem Biol. 16(6):630–634. https://doi.org/10.1038/s41589-020-0504-2
Nikolskaya II, Lopatina NG, Chaplygina NM, Debov SS (1976) The host specificity system in Escherichia coli SK. Mol Cell Biochem. 13(2):79–87
Nikolskaya II, Lopatina NG, Debov SS (1981) On heterogeneity of DNA methylases from Escherichia coli SK cells. Mol Cell Biochem. 35(1):3–10
Niu Y, Zhao X, Wu YS, Li MM, Wang XJ, Yang YG (2013) N6-methyl-adenosine (m6A) in RNA: an old modification with a novel epigenetic function. Genom Proteom Bioinf 11(1):8–17. https://doi.org/10.1016/j.gpb.2012.12.002
Nordstrand LM, Svard J, Larsen E, Nilsen A, Ougland R, Furu K et al (2010) Mice lacking Alkbh1 display sex-ratio distortion and unilateral eye defects. PLoS One. 5(11):e13827. https://doi.org/10.1371/journal.pone.0013827
O‘Brown ZK, Boulias K, Wang J, Wang SY, O‘Brown NM, Hao Z et al (2019) Sources of artifact in measurements of 6mA and 4mC abundance in eukaryotic genomic DNA. BMC Genomics. 20(1):445. https://doi.org/10.1186/s12864-019-5754-6
Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 99(3):247–257
Pacini CE, Bradshaw CR, Garrett NJ, Koziol MJ (2019) Characteristics and homogeneity of N6-methylation in human genomes. Sci Rep. 9(1):5185. https://doi.org/10.1038/s41598-019-41601-7
Parfrey LW, Lahr DJ, Knoll AH, Katz LA (2011) Estimating the timing of early eukaryotic diversification with multigene molecular clocks. Proc Nat Acad Sci U S A 108(33):13624–13629. https://doi.org/10.1073/pnas.1110633108
Peer E, Rechavi G, Dominissini D (2017) Epitranscriptomics: regulation of mRNA metabolism through modifications. Curr Opin Chem Biol. 41:93–98. https://doi.org/10.1016/j.cbpa.2017.10.008
Peng S, Padva A, LeBreton PR (1976) Ultraviolet photoelectron studies of biological purines: the valence electronic structure of adenine. Proc Nat Acad Sci U S A 73(9):2966–2968
Pogolotti AL Jr, Ono A, Subramaniam R, Santi DV (1988) On the mechanism of DNA-adenine methylase. J Biol Chem 263(16):7461–7464
Pomraning KR, Smith KM, Freitag M (2009) Genome-wide high throughput analysis of DNA methylation in eukaryotes. Methods. 47(3):142–150. https://doi.org/10.1016/j.ymeth.2008.09.022
Posfai G, Szybalski W (1988) A simple method for locating methylated bases in DNA using class-IIS restriction enzymes. Gene. 74(1):179–181
Pratt K, Hattman S (1983) Nucleosome phasing in Tetrahymena macronuclei. J Protozool. 30(3):592–598
Privat E, Sowers LC (1996) Photochemical deamination and demethylation of 5-methylcytosine. Chem Res Toxicol. 9(4):745–750. https://doi.org/10.1021/tx950182o
Proffitt JH, Davie JR, Swinton D, Hattman S (1984) 5-Methylcytosine is not detectable in Saccharomyces cerevisiae DNA. Mol Cell Biol. 4(5):985–988
Pukkila PJ, Peterson J, Herman G, Modrich P, Meselson M (1983) Effects of high levels of DNA adenine methylation on methyl-directed mismatch repair in Escherichia coli. Genetics. 104(4):571–582
Quignard E, Fazakerley GV, Teoule R, Guy A, Guschlbauer W (1985) Consequences of methylation on the amino group of adenine. A proton two-dimensional NMR study of d(GGATATCC) and d(GGm6ATATCC). Eur J Biochem. 152(1):99–105
Rae PM (1976) Hydroxymethyluracil in eukaryote DNA: a natural feature of the pyrrophyta (dinoflagellates). Science (New York, NY) 194(4269):1062–1064
Rae PM, Spear BB (1978) Macronuclear DNA of the hypotrichous ciliate Oxytricha fallax. Proc Nat Acad Sci U S A 75(10):4992–4996
Ratel D, Ravanat JL, Charles MP, Platet N, Breuillaud L, Lunardi J et al (2006) Undetectable levels of N6-methyl adenine in mouse DNA: Cloning and analysis of PRED28, a gene coding for a putative mammalian DNA adenine methyltransferase. FEBS Lett. 580(13):3179–3184. https://doi.org/10.1016/j.febslet.2006.04.074
Razin A, Razin S (1980) Methylated bases in mycoplasmal DNA. Nucleic Acids Res. 8(6):1383–1390
Reich NO, Mashhoon N (1991) Kinetic mechanism of the EcoRI DNA methyltransferase. Biochemistry. 30(11):2933–2939
Robbins-Manke JL, Zdraveski ZZ, Marinus M, Essigmann JM (2005) Analysis of global gene expression and double-strand-break formation in DNA adenine methyltransferase- and mismatch repair-deficient Escherichia coli. J Bacteriol. 187(20):7027–7037. https://doi.org/10.1128/JB.187.20.7027-7037.2005
Roberts D, Hoopes BC, McClure WR, Kleckner N (1985) IS10 transposition is regulated by DNA adenine methylation. Cell. 43(1):117–130
Rogers JC, Rogers SW (1995) Comparison of the effects of N6-methyldeoxyadenosine and N5-methyldeoxycytosine on transcription from nuclear gene promoters in barley. Plant J. 7(2):221–233
Rogers SD, Rogers ME, Saunders G, Holt G (1986) Isolation of mutants sensitive to 2-aminopurine and alkylating agents and evidence for the role of DNA methylation in Penicillium chrysogenum. Curr Genet. 10(7):557–560
Romanov GA, Vanyushin BF (1981) Methylation of reiterated sequences in mammalian DNAs. Effects of the tissue type, age, malignancy and hormonal induction. Biochim Biophys Acta. 653(2):204–218
Russell DW, Hirata RK (1989) The detection of extremely rare DNA modifications. Methylation in dam- and hsd- Escherichia coli strains. J Biol Chem 264(18):10787–10794
Sanchez-Romero MA, Olivenza DR, Gutierrez G, Casadesus J (2020) Contribution of DNA adenine methylation to gene expression heterogeneity in Salmonella enterica. Nucleic Acids Res. 48(21):11857–11867. https://doi.org/10.1093/nar/gkaa730
Saparbaev M, Laval J (1994) Excision of hypoxanthine from DNA containing dIMP residues by the Escherichia coli, yeast, rat, and human alkylpurine DNA glycosylases. Proc Nat Acad Sci U S A 91(13):5873–5877
Sarnacki SH, Castaneda Mdel R, Noto Llana M, Giacomodonato MN, Valvano MA, Cerquetti MC (2013) Dam methylation participates in the regulation of PmrA/PmrB and RcsC/RcsD/RcsB two component regulatory systems in Salmonella enterica serovar Enteritidis. PLoS One. 8(2):e56474. https://doi.org/10.1371/journal.pone.0056474
Sater MR, Lamelas A, Wang G, Clark TA, Roltgen K, Mane S et al (2015) DNA Methylation Assessed by SMRT Sequencing Is Linked to Mutations in Neisseria meningitidis Isolates. PLoS One. 10(12):e0144612. https://doi.org/10.1371/journal.pone.0144612
Schiffers S, Ebert C, Rahimoff R, Kosmatchev O, Steinbacher J, Bohne AV et al (2017) Quantitative LC-MS provides no evidence for m(6) dA or m(4) dC in the genome of mouse embryonic stem cells and tissues. Angew Chem Int Ed Engl. 56(37):11268–11271. https://doi.org/10.1002/anie.201700424
Sedgwick B, Bates PA, Paik J, Jacobs SC, Lindahl T (2007) Repair of alkylated DNA: recent advances. DNA Repair (Amst). 6(4):429–442. https://doi.org/10.1016/j.dnarep.2006.10.005
Shah K, Cao W, Ellison CE (2019) Adenine methylation in drosophila is associated with the tissue-specific expression of developmental and regulatory genes. G3 (Bethesda) 9(6):1893–1900. https://doi.org/10.1534/g3.119.400023
Shapiro R, Klein RS (1966) The deamination of cytidine and cytosine by acidic buffer solutions. Mutagenic implications. Biochemistry. 5(7):2358–2362
Shen L, Song CX, He C, Zhang Y (2014) Mechanism and function of oxidative reversal of DNA and RNA methylation. Annu Rev Biochem. 83:585–614. https://doi.org/10.1146/annurev-biochem-060713-035513
Slater S, Wold S, Lu M, Boye E, Skarstad K, Kleckner N (1995) E. coli SeqA protein binds oriC in two different methyl-modulated reactions appropriate to its roles in DNA replication initiation and origin sequestration. Cell. 82(6):927–936
Smith JD, Arber W, Kuhnlein U (1972) Host specificity of DNA produced by Escherichia coli. XIV. The role of nucleotide methylation in in vivo B-specific modification. J Mol Biol. 63(1):1–8
Srivastava R, Gopinathan KP, Ramakrishnan T (1981) Deoxyribonucleic acid methylation in mycobacteria. J Bacteriol. 148(2):716–719
Stein R, Gruenbaum Y, Pollack Y, Razin A, Cedar H (1982) Clonal inheritance of the pattern of DNA methylation in mouse cells. Proc Nat Acad Sci U S A 79(1):61–65
Stephens C, Reisenauer A, Wright R, Shapiro L (1996) A cell cycle-regulated bacterial DNA methyltransferase is essential for viability. Proc Nat Acad Sci U S A 93(3):1210–1214
Sternglanz H, Bugg CE (1973) Conformation of N6-methyladenine, a base involved in DNA modification: restriction processes. Science (New York, NY) 182(4114):833–834
Su SS, Modrich P (1986) Escherichia coli mutS-encoded protein binds to mismatched DNA base pairs. Proc Nat Acad Sci U S A 83(14):5057–5061
Sugimoto K, Takeda S, Hirochika H (2003) 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. 36(4):550–564
Sun Q, Huang S, Wang X, Zhu Y, Chen Z, Chen D (2015) N(6) -methyladenine functions as a potential epigenetic mark in eukaryotes. Bioessays. 37(11):1155–1162. https://doi.org/10.1002/bies.201500076
Sundheim O, Talstad VA, Vagbo CB, Slupphaug G, Krokan HE (2008) AlkB demethylases flip out in different ways. DNA Repair (Amst). 7(11):1916–1923. https://doi.org/10.1016/j.dnarep.2008.07.015
Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y et al (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science (New York, NY) 324(5929):930–935. https://doi.org/10.1126/science.1170116
Tawa R, Ueno S, Yamamoto K, Yamamoto Y, Sagisaka K, Katakura R et al (1992) Methylated cytosine level in human liver DNA does not decline in aging process. Mech Ageing Dev 62(3):255–261
Theil EC, Zamenhof S (1963) Studies on 6-Methylaminopurine (6-Methyladenine) in Bacterial Deoxyribonucleic Acid. J Biol Chem 238:3058–3064
Trewick SC, Henshaw TF, Hausinger RP, Lindahl T, Sedgwick B (2002) Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage. Nature. 419(6903):174–178. https://doi.org/10.1038/nature00908
Tronche F, Rollier A, Bach I, Weiss MC, Yaniv M (1989) 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. 9(11):4759–4766
Tsuchiya H, Matsuda T, Harashima H, Kamiya H (2005) Cytokine induction by a bacterial DNA-specific modified base. Biochem Biophys Res Commun. 326(4):777–781. https://doi.org/10.1016/j.bbrc.2004.11.115
Unger G, Venner H (1966) Remarks on minor bases in spermatic desoxyribonucleic acid. Hoppe Seylers Z Physiol Chem. 344(4):280–283
Urbonavicius J, Skouloubris S, Myllykallio H, Grosjean H (2005) Identification of a novel gene encoding a flavin-dependent tRNA:m5U methyltransferase in bacteria--evolutionary implications. Nucleic Acids Res. 33(13):3955–3964. https://doi.org/10.1093/nar/gki703
Urig S, Gowher H, Hermann A, Beck C, Fatemi M, Humeny A et al (2002) The Escherichia coli dam DNA methyltransferase modifies DNA in a highly processive reaction. J Mol Biol. 319(5):1085–1096. https://doi.org/10.1016/S0022-2836(02)00371-6
van den Born E, Omelchenko MV, Bekkelund A, Leihne V, Koonin EV, Dolja VV et al (2008) Viral AlkB proteins repair RNA damage by oxidative demethylation. Nucleic Acids Res. 36(17):5451–5461. https://doi.org/10.1093/nar/gkn519
Van Etten JL, Schuster AM, Girton L, Burbank DE, Swinton D, Hattman S (1985) DNA methylation of viruses infecting a eukaryotic Chlorella-like green alga. Nucleic Acids Res. 13(10):3471–3478
Vanyushin BF, Belozersky AN, Kokurina NA, Kadirova DX (1968) 5-methylcytosine and 6-methylamino-purine in bacterial DNA. Nature. 218(5146):1066–1067
Vanyushin BF, Tkacheva SG, Belozersky AN (1970) Rare bases in animal DNA. Nature. 225(5236):948–949
von Freiesleben U, Rasmussen KV, Schaechter M (1994) SeqA limits DnaA activity in replication from oriC in Escherichia coli. Mol Microbiol. 14(4):763–772
Wagner I, Capesius I (1981) Determination of 5-methylcytosine from plant DNA by high-performance liquid chromatography. Biochim Biophys Acta. 654(1):52–56
Wallecha A, Munster V, Correnti J, Chan T, van der Woude M (2002) Dam- and OxyR-dependent phase variation of agn43: essential elements and evidence for a new role of DNA methylation. J Bacteriol. 184(12):3338–3347
Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D et al (2014) N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 505(7481):117–120. https://doi.org/10.1038/nature12730
Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H et al (2015) N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell. 161(6):1388–1399. https://doi.org/10.1016/j.cell.2015.05.014
Wang W, Xu L, Hu L, Chong J, He C, Wang D (2017) Epigenetic DNA modification N(6)-Methyladenine causes site-specific RNA polymerase II transcriptional pausing. J Am Chem Soc. 139(41):14436–14442. https://doi.org/10.1021/jacs.7b06381
Wang SY, Mao H, Shibuya H, Uzawa S, O‘Brown ZK, Wesenberg S et al (2019) The demethylase NMAD-1 regulates DNA replication and repair in the Caenorhabditis elegans germline. PLoS Genet. 15(7):e1008252. https://doi.org/10.1371/journal.pgen.1008252
Weber M, Davies JJ, Wittig D, Oakeley EJ, Haase M, Lam WL et al (2005) Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet 37(8):853–862. https://doi.org/10.1038/ng1598
Wei YF, Carter KC, Wang RP, Shell BK (1996) 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. 24(5):931–937
Willis DB, Granoff A (1980) Frog virus 3 DNA is heavily methylated at CpG sequences. Virology. 107(1):250–257
Wion D, Casadesus J (2006) N6-methyl-adenine: an epigenetic signal for DNA-protein interactions. Nat Rev Microbiol. 4(3):183–192. https://doi.org/10.1038/nrmicro1350
Wold S, Boye E, Slater S, Kleckner N, Skarstad K (1998) Effects of purified SeqA protein on oriC-dependent DNA replication in vitro. EMBO J 17(14):4158–4165. https://doi.org/10.1093/emboj/17.14.4158
Woodcock CB, Yu D, Hajian T, Li J, Huang Y, Dai N et al (2019) Human MettL3-MettL14 complex is a sequence-specific DNA adenine methyltransferase active on single-strand and unpaired DNA in vitro. Cell Discov. 5:63. https://doi.org/10.1038/s41421-019-0136-4
Wu JC, Santi DV (1987) Kinetic and catalytic mechanism of HhaI methyltransferase. J Biol Chem 262(10):4778–4786
Wu TP, Wang T, Seetin MG, Lai Y, Zhu S, Lin K et al (2016) DNA methylation on N-adenine in mammalian embryonic stem cells. Nature. https://doi.org/10.1038/nature17640
Wyatt GR (1950) Occurrence of 5-methylcytosine in nucleic acids. Nature. 166(4214):237–238
Wyatt GR, Cohen SS (1952) A new pyrimidine base from bacteriophage nucleic acids. Nature. 170(4338):1072–1073
Xiao CL, Zhu S, He M, Chen D, Zhang Q, Chen Y et al (2018) N(6)-Methyladenine DNA modification in the human genome. Mol Cell 71(2):306–318. e7. https://doi.org/10.1016/j.molcel.2018.06.015
Xie Q, Wu TP, Gimple RC, Li Z, Prager BC, Wu Q et al (2018) N(6)-methyladenine DNA modification in glioblastoma. Cell. 175(5):1228–1243. e20. https://doi.org/10.1016/j.cell.2018.10.006
Xiong J, Ye TT, Ma CJ, Cheng QY, Yuan BF, Feng YQ (2019) N 6-Hydroxymethyladenine: a hydroxylation derivative of N6-methyladenine in genomic DNA of mammals. Nucleic Acids Res. 47(3):1268–1277. https://doi.org/10.1093/nar/gky1218
Yamaki H, Ohtsubo E, Nagai K, Maeda Y (1988) The oriC unwinding by dam methylation in Escherichia coli. Nucleic Acids Res. 16(11):5067–5073
Yang CG, Yi C, Duguid EM, Sullivan CT, Jian X, Rice PA et al (2008) Crystal structures of DNA/RNA repair enzymes AlkB and ABH2 bound to dsDNA. Nature. 452(7190):961–965. https://doi.org/10.1038/nature06889
Yao B, Cheng Y, Wang Z, Li Y, Chen L, Huang L et al (2017) DNA N6-methyladenine is dynamically regulated in the mouse brain following environmental stress. Nat Commun. 8(1):1122. https://doi.org/10.1038/s41467-017-01195-y
Yao B, Li Y, Wang Z, Chen L, Poidevin M, Zhang C et al (2018) Active N(6)-Methyladenine Demethylation by DMAD Regulates Gene Expression by Coordinating with Polycomb Protein in Neurons. Mol Cell 71(5):848–857. e6. https://doi.org/10.1016/j.molcel.2018.07.005
Ye P, Luan Y, Chen K, Liu Y, Xiao C, Xie Z (2017) MethSMRT: an integrative database for DNA N6-methyladenine and N4-methylcytosine generated by single-molecular real-time sequencing. Nucleic Acids Res. 45(D1):D85–DD9. https://doi.org/10.1093/nar/gkw950
Yoder JA, Soman NS, Verdine GL, Bestor TH (1997) DNA (cytosine-5)-methyltransferases in mouse cells and tissues. Studies with a mechanism-based probe. J Mol Biol. 270(3):385–395. https://doi.org/10.1006/jmbi.1997.1125
Yue Y, Liu J, He C (2015) RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation. Genes Dev 29(13):1343–1355. https://doi.org/10.1101/gad.262766.115
Yuki H, Kawasaki H, Imayuki A, Yajima T (1979) Determination of 6-methyladenine in DNA by high-performance liquid chromatography. J Chromatogr. 168(2):489–494
Zaccara S, Ries RJ, Jaffrey SR (2019) Reading, writing and erasing mRNA methylation. Nature Rev 20(10):608–624. https://doi.org/10.1038/s41580-019-0168-5
Zaleski P, Wojciechowski M, Piekarowicz A (2005) The role of Dam methylation in phase variation of Haemophilus influenzae genes involved in defence against phage infection. Microbiology. 151(Pt 10):3361–3369. https://doi.org/10.1099/mic.0.28184-0
Zelinkova E, Paulicek M, Zelinka J (1990) Modification methylase M.Sau3239I from Streptomyces aureofaciens 3239. FEBS Lett. 271(1-2):147–148
Zhang G, Huang H, Liu D, Cheng Y, Liu X, Zhang W et al (2015) N(6)-methyladenine DNA modification in Drosophila. Cell. 161(4):893–906. https://doi.org/10.1016/j.cell.2015.04.018
Zhang Q, Liang Z, Cui X, Ji C, Li Y, Zhang P et al (2018) N(6)-Methyladenine DNA methylation in Japonica and Indica rice genomes and its association with gene expression, plant development, and stress responses. Mol Plant. 11(12):1492–1508. https://doi.org/10.1016/j.molp.2018.11.005
Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ et al (2013) ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 49(1):18–29. https://doi.org/10.1016/j.molcel.2012.10.015
Zhou J, Wan J, Gao X, Zhang X, Jaffrey SR, Qian SB (2015) Dynamic m(6)A mRNA methylation directs translational control of heat shock response. Nature. 526(7574):591–594. https://doi.org/10.1038/nature15377
Zhu S, Beaulaurier J, Deikus G, Wu T, Strahl M, Hao Z et al (2018) Mapping and characterizing N6-methyladenine in eukaryotic genomes using single molecule real-time sequencing. Genome Res. https://doi.org/10.1101/gr.231068.117
Acknowledgments
We thank S. Burger, N. O’Brown, and E. Pollina for the critical reading of the manuscript. We thank M.H. Rothi for help generating heat maps in Fig. 8.1. We thank C. He for helpful discussions. The work from the Greer laboratory is supported by grants from the NIH (DP2AG055947 and R01AI151215). Z.K.O. was supported by 5T32HD7466-19. We apologize for literature omitted owing to space limitations.
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O’Brown, Z.K., Greer, E.L. (2022). N6-methyladenine: A Rare and Dynamic DNA Mark. In: Jeltsch, A., Jurkowska, R.Z. (eds) DNA Methyltransferases - Role and Function. Advances in Experimental Medicine and Biology, vol 1389. Springer, Cham. https://doi.org/10.1007/978-3-031-11454-0_8
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