Thymine-DNA glycosylase and G to A transition mutations at CpG sites.
About 23% of mutations in hereditary human diseases and 24% of mutations in p53 in human cancers are G to A transitions at sites of cytosine methylation suggesting that these sites are either foci for DNA damage, or foci for damage that is poorly repaired. Thymine produced at these sites by the hydrolytic deamination of 5-methylcytosine is removed by thymine-DNA glycosylase. Thymine-DNA glycosylase will also remove 3,N(4)-ethenocytosine and uracil from DNA. The action of this enzyme is limited by its very low k(cat) and by tight binding to the apurinic site produced when the thymine is removed. These properties of the enzyme suggest that the inefficiency of the base excision repair pathway that it initiates may be the underlying cause of the prevalence of these mutations.
Waters
T R
TR
Department of Biochemistry and Molecular Biology, University College London, London, UK. t.waters@biochem.ucl.ac.uk
Swann
P F
PF
D004249:DNA Damage; D004260:DNA Repair; D043224:Deoxyribonuclease (Pyrimidine Dimer); D004706:Endodeoxyribonucleases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D017354:Point Mutation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013941:Thymine / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D016159:Tumor Suppressor Protein p53; D004706:Endodeoxyribonucleases; D043224:Deoxyribonuclease (Pyrimidine Dimer); D013941:Thymine