DNA Methylation: Basic Mechanisms

Volume 301 of the series Current Topics in Microbiology and Immunology pp 283-315

Cytosine Methylation and DNA Repair

  • C. P. WalshAffiliated withCentre for Molecular Biosciences, School of Biomedical Sciences, University of Ulster
  • , G. L. XuAffiliated withLaboratory for Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences

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Cytosine methylation is a common form of post-replicative DNA modification seen in both bacteria and eukaryotes. Modified cytosines have long been known to act as hotspots formutations due to the high rate of spontaneous deamination of this base to thymine, resulting in a G/T mismatch. This will be fixed as a C→T transition after replication if not repaired by the base excision repair (BER) pathway or specific repair enzymes dedicated to this purpose. This hypermutability has led to depletion of the target dinucleotide CpG outside of special CpG islands in mammals, which are normally unmethylated. We review the importance of C→T transitions at nonisland CpGs in human disease: When these occur in the germline, they are a common cause of inherited diseases such as epidermolysis bullosa and mucopolysaccharidosis, while in the soma they are frequently found in the genes for tumor suppressors such as p53 and the retinoblastoma protein, causing cancer. We also examine the specific repair enzymes involved, namely the endonuclease Vsr in Escherichia coli and two members of the uracil DNA glycosylase (UDG) superfamily in mammals, TDG and MBD4. Repair brings its own problems, since it will require remethylation of the replacement cytosine, presumably coupling repair to methylation by either the maintenance methylase Dnmt1 or a de novo enzyme such as Dnmt3a. Uncoupling of methylation from repair may be one way to remove methylation from DNA. We also look at the possible role of specific cytosine deaminases such as Aid and Apobec in accelerating deamination of methylcytosine and consequent DNA demethylation.