Cytosine methylation and DNA repair

Research output: Chapter in Book/Report/Conference proceedingChapter

82 Citations (Scopus)

Abstract

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.
LanguageEnglish
Title of host publicationDNA METHYLATION: BASIC MECHANISMS
Place of PublicationHeidelberg
Pages283-315
Volume301
Publication statusPublished - 2006

Publication series

NameCURRENT TOPICS IN MICROBIOLOGY AND IMMUNOLOGY
PublisherSpringer-Verlag

Fingerprint

Cytosine
DNA Repair
Methylation
Deamination
Mammals
Enzymes
Cytosine Deaminase
Uracil-DNA Glycosidase
Mucopolysaccharidoses
Epidermolysis Bullosa
Retinoblastoma Protein
CpG Islands
Thymine
DNA
Carisoprodol
DNA Methylation
Tumor Suppressor Genes
Eukaryota
Maintenance
Escherichia coli

Cite this

Walsh, C., & Xu, GL. (2006). Cytosine methylation and DNA repair. In DNA METHYLATION: BASIC MECHANISMS (Vol. 301, pp. 283-315). (CURRENT TOPICS IN MICROBIOLOGY AND IMMUNOLOGY). Heidelberg.
Walsh, Colum ; Xu, GL. / Cytosine methylation and DNA repair. DNA METHYLATION: BASIC MECHANISMS. Vol. 301 Heidelberg, 2006. pp. 283-315 (CURRENT TOPICS IN MICROBIOLOGY AND IMMUNOLOGY).
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Walsh, C & Xu, GL 2006, Cytosine methylation and DNA repair. in DNA METHYLATION: BASIC MECHANISMS. vol. 301, CURRENT TOPICS IN MICROBIOLOGY AND IMMUNOLOGY, Heidelberg, pp. 283-315.

Cytosine methylation and DNA repair. / Walsh, Colum; Xu, GL.

DNA METHYLATION: BASIC MECHANISMS. Vol. 301 Heidelberg, 2006. p. 283-315 (CURRENT TOPICS IN MICROBIOLOGY AND IMMUNOLOGY).

Research output: Chapter in Book/Report/Conference proceedingChapter

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T1 - Cytosine methylation and DNA repair

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N2 - 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.

AB - 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.

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Walsh C, Xu GL. Cytosine methylation and DNA repair. In DNA METHYLATION: BASIC MECHANISMS. Vol. 301. Heidelberg. 2006. p. 283-315. (CURRENT TOPICS IN MICROBIOLOGY AND IMMUNOLOGY).