Molecular Enzymology of Mammalian DNA Methyltransferases
DNA methylation is an essential modification of DNA in mammals that is involved in gene regulation, development, genome defence and disease. In mammals 3 families of DNA methyltransferases (MTases) comprising (so far) 4 members have been found: Dnmt1, Dnmt2, Dnmt3A and Dnmt3B. In addition, Dnmt3L has been identified as a stimulator of the Dnmt3A and Dnmt3B enzymes. In this review the enzymology of the mammalian DNA MTases is described, starting with a depiction of the catalytic mechanism that involves covalent catalysis and base flipping. Subsequently, important mechanistic features of the mammalian enzyme are discussed including the specificity of Dnmt1 for hemimethylated target sites, the target sequence specificity of Dnmt3A, Dnmt3B and Dnmt2 and the flanking sequence preferences of Dnmt3A and Dnmt3B. In addition, the processivity of the methylation reaction by Dnmt1, Dnmt3A and Dnmt3B is reviewed. Finally, the control of the catalytic activity of mammalian MTases is described that includes the regulation of the activity ofDnmt1 by its N-terminal domain and the interaction of Dnmt3A and Dnmt3B with Dnmt3L. The allosteric activation of Dnmt1 for methylation at unmodified sites is described. Wherever possible, correlations between the biochemical properties of the enzymes and their physiological functions in the cell are indicated.
Unable to display preview. Download preview PDF.
- Aapola U, Kawasaki K, Scott HS, Ollila J, Vihinen M, Heino M, Shintani A, Minoshima S, Krohn K, Antonarakis SE, Shimizu N, Kudoh J, Peterson P (2000) Isolation and initial characterization of a novel zinc finger gene, DNMT3L, on 21q22.3, related to the cytosine-5-methyltransferase 3 gene family. Genomics 65:293–298CrossRefPubMedGoogle Scholar
- Bacolla A, Pradhan S, Larson JE, Roberts RJ, Wells RD (2001) Recombinanthuman DNA (cytosine-5) methyltransferase. III. Allosteric control, reaction order, and influence of plasmid topology and triplet repeat length on methylation of the fragile X CGG.CCG sequence. J Biol Chem 276:18605–18613PubMedGoogle Scholar
- Fatemi M, Hermann A, Pradhan S, 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. J Mol Biol 309:1189–1199CrossRefPubMedGoogle Scholar
- Gowher H, Jeltsch A (2004) Mechanism of inhibition of DNA methyltransferases by cytidine analogs in cancer therapy. Cancer Biol Ther 3Google Scholar
- Handa V, Jeltsch A (2005) Profound flanking sequence preference of Dnmt3a and Dnmt3b mammalian methyltransferases shape the human epigenome. JMol Biol 348:1103–1112Google Scholar
- Reither S, Li F, Gowher H, Jeltsch A (2003) Catalytic mechanism of DNA-(cytosine-C5)-methyltransferases revisited: covalent intermediate formation is not essential for methyl group transfer by the murine Dnmt3a enzyme. JMol Biol 329:675–684Google Scholar