DNA Methylation: Enzymology

Moshe Szyf, McGill University, Montreal, Canada

Published online: January 2006

DOI: 10.1038/npg.els.0006156

In vertebrates, the dinucleotide sequence CG is methylated. The DNA methylation reaction is catalyzed by DNA methyltransferases, which use S-adenosyl-methionine as the methyl donor. In addition to DNA methyltransferases, chromatin modifying and remodeling proteins are involved in creating and replicating DNA methylation patterns. Data suggest that demethylases, enzymes that remove methyl groups from DNA, are involved in shaping DNA methylation patterns.

Keywords: 5-methylcytosine; DNA methylation; chromatin structure; DNA methyltransferases; demethylase; de novo methylation

Figure 1. DNA methyltransferases catalyze methylation of DNA. In vertebrate DNA, the reactants of DNA methylation are a cytosine located in the sequence CG and AdoMet, the methyl (CH3) donor. The products of the reaction are methylcytosine at the 5¢ position of the cytosine ring and AdoHcy.
Figure 2. DNA methylation reactions. During DNA replication, the maintenance DNA methyltransferase copies the pattern of methylation of the parental strand (pale gray) onto the nascent strand (black). CG sites are indicated by the filled circles. Methylated sites are denoted by CH3. De novo methylation does not require replication and results in the addition of methyl groups to CG sites that were not previously methylated. Demethylation involves removal of a methyl group from DNA catalyzed by a demethylase. It does not require DNA replication.
close
 References
    Bhattacharya SK, Ramchandani S, Cervoni N and Szyf M (1999) A mammalian protein with specific demethylase activity for mCpG DNA. Nature 397: 579–583.
    Cheng X, Kumar S, Posfai J, Pflugrath JW and Roberts RJ (1993) Crystal structure of the HhaI DNA methyltransferase complexed with S-adenosyl-l-methionine. Cell 74: 299–307.
    Di CL, Raker VA, Corsaro M, et al. (2002) Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295: 1079–1082.
    Fuks F, Burgers WA, Brehm A, Hughes-Davies L and Kouzarides T (2000) DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nature Genetics 24: 88–91.
    Jackson JP, Lindroth AM, Cao X and Jacobsen SE (2002) Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase. Nature 416: 556–560.
    Okano M, Bell DW, Haber DA and Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novomethylation and mammalian development. Cell 99: 247–257.
    Razin A and Cedar H (1977) Distribution of 5-methylcytosine in chromatin. Proceedings of the National Academy of Sciences of the United States of America 74: 2725–2728.
    Razin A and Riggs AD (1980) DNA methylation and gene function. Science 210: 604–610.
    Tamaru H and Selker EU (2001) A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 414: 277–283.
    Zhu B, Zheng Y, Hess D, et al. (2000) 5-methylcytosine-DNA glycosylase activity is present in a cloned G/T mismatch DNA glycosylase associated with the chicken embryo DNA demethylation complex. Proceedings of the National Academy of Sciences of the United States of America 97: 5135–5139.
 Further Reading
    Ben-Porath I and Cedar H (2001) Epigenetic crosstalk. Molecular Cell 8: 933–935.
    Richards EJ and Elgin SC (2002) Epigenetic codes for heterochromatin formation and silencing: rounding up the usual suspects. Cell 108: 489–500.
    Bestor TH (1988) Cloning of a mammalian DNA methyltransferase. Gene 74: 9–12.
    Cervoni N and Szyf M (2001) Demethylase activity is directed by histone acetylation. Journal of Biological Chemistry 276: 40778–40787.
    Cheng X and Roberts RJ (2001) AdoMet-dependent methylation, DNA methyltransferases and base flipping. Nucleic Acids Research 29: 3784–3795.
    Fatemi M, Hermann A, Pradhan S and Jeltsch A (2001) The activity of the murine DNA methyltransferase Dnmt1 is controlled by interaction of the catalytic domain with the N-terminal part of the enzyme leading to an allosteric activation of the enzyme after binding to methylated DNA. Journal of Molecular Biology 309: 1189–1199.
    Gendrel AV, Lippman Z, Yordan C, Colot V and Martienssen RA (2002) Dependence of heterochromatic histone H3 methylation patterns on the Arabidopsisgene DDM1. Science 297: 1871–1873.
    Gibbons RJ, McDowell TL, Raman S, et al. (2000) Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation. Nature Genetics 24: 368–371.
    Kafri T, Gao X and Razin A (1993) Mechanistic aspects of genome-wide demethylation in the preimplantation mouse embryo. Proceedings of the National Academy of Sciences of the United States of America 90: 10558–10562.
    Kim GD, Ni J, Kelesoglu N, Roberts RJ and Pradhan S (2002) Co-operation and communication between the human maintenance and de novoDNA (cytosine-5) methyltransferases. The EMBO Journal 21: 4183–4195.
    Li E, Bestor TH and Jaenisch R (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69: 915–926.
    Liang G, Chan MF, Tomigahara Y, et al. (2002) Cooperativity between DNA methyltransferases in the maintenance methylation of repetitive elements. Molecular and Cellular Biology 22: 480–491.
    Oswald J, Engemann S, Lane N, et al. (2000) Active demethylation of the paternal genome in the mouse zygote. Current Biology 10: 475–478.
    Robertson KD, Ait-Si-Ali S, Yokochi T, et al. (2000) DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nature Genetics 25: 338–342.
    Wu JC and Santi DV (1987) Kinetic and catalytic mechanism of Hha I methyltransferase. Journal of Biological Chemistry 262: 4778–4786.
 Web Links
    ePath DNA (cytosine-5-)-methyltransferase 1 (DNMT1); LocusID: 1786. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=1786
    ePath DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A); LocusID: 1788. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=1788
    ePath DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B); LocusID: 1789. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=1789
    ePath DNA (cytosine-5-)-methyltransferase 3-likea (DNMT3L); LocusID: 22947. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=22947
    ePath Histone deacetylase 1 (HDAC1); LocusID: 3065. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=3065
    ePath DNA (cytosine-5-)-methyltransferase 1 (DNMT1); MIM number: 126375. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?126375
    ePath DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A); MIM number: 602769. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?602769
    ePath DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B); MIM number: 602900. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?602900
    ePath DNA (cytosine-5-)-methyltransferase 3-like (DNMT3L); MIM number: 606588. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?606588
    ePath Histone deacetylase 1 (HDAC1); MIM number: 601241. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?601241

Related Sub-Topics:

Chromosomes and Chromatin Modifications | DNA Structure and Function | Enzymes: Structure and Action Mechanism | Nucleic Acids: Structure, Function, Metabolism
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: DNA Methylation: Enzymology
 
How to Cite close
Szyf, Moshe(Jan 2006) DNA Methylation: Enzymology. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0006156]