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Cytosine methylation and DNA repair

Walsh, Colum and Xu, GL (2006) Cytosine methylation and DNA repair. In: DNA METHYLATION: BASIC MECHANISMS. Springer-Verlag, Heidelberg, pp. 283-315. ISBN 9783540291145 [Book section]

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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 for mutations 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 non-island 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.

Item Type:Book section
Faculties and Schools:Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Genomic Medicine
ID Code:21710
Deposited By: Professor Colum Walsh
Deposited On:04 Apr 2012 12:54
Last Modified:10 May 2017 10:17

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