DNA Methylation: Enzymology

Abstract

Abstract Methylated bases (C5‐methylcytosine, N4‐methylcytosine and N6‐methyladenine) are found in the DNA of most species, where they play important biological roles. There exist two families of DNA methyltransferases with specificity for methylation of the C5 position of cytosine or exocyclic amino groups of cytosine or adenine. They all use S ‐adenosyl‐l‐methionine as the methyl group donor and contain a catalytic domain with a similar fold. In bacteria, methylation of DNA is used to distinguish self and foreign DNA, to direct post‐replicative mismatch repair, co‐ordinate DNA replication and cell cycle and for regulation of gene expression. In vertebrates, DNA methylation is established by three DNA methyltransferases (Dnmt1, Dnmt3a and Dnmt3b) in a cell‐type‐specific pattern, mainly at the CG sites. It functions as an epigenetic mark and is involved in the regulation of chromatin accessibility in many biological contexts. Bacterial DNA methyltransferases are mainly directed by the DNA sequence of their target site, whereas mammalian and plant Dnmts are recruited and regulated by several factors and other epigenetic signals, including modification of histone tails or RNA molecules. Key Concepts DNA methylation adds information to the DNA that is not encoded in the DNA sequence. DNA methyltransferases use AdoMet as methyl group donor and flip their target base out of the DNA helix. DNA methylation in bacteria reflects the sequence specificity of the bacterial methyltransferases, whereas eukaryotic enzymes are targeted and regulated by a network of different mechanisms. Maintenance of mammalian DNA methylation patterns is mainly encoded in the palindromic nature of the CG site and is coupled to DNA replication. Eukaryotic DNA methyltransferases are recruited by specific histone modifications generating a network of interconnected epigenetic signals.