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The Mechanism Of Maintenance Of DNA Methylation Patterns During Base Excision Repair

Posted on:2007-05-21Degree:DoctorType:Dissertation
Country:ChinaCandidate:Y Q LiFull Text:PDF
GTID:1100360215955092Subject:Biochemistry and Molecular Biology
Abstract/Summary:PDF Full Text Request
While methylcytosines serve as the fifth base encoding epigenetic information, they are also a dangerous endogenous mutagen due to their intrinsic instability. Methylcytosine undergoes spontaneous deamination, at a rate much higher than cytosine, to generate thymine. In mammals, two thymine DNA glycosylases TDG (thymine DNA glycosylase) and MBD4 (methyl-CpG binding domain 4), have evolved to counteract the mutagenic effect of methylcytosines. Both recognize G/T mismatches arising from methylcytosine deamination and initiate base-excision repair that corrects them to G/C pairs. However, the mechanism by which the methylation status of the repaired cytosines is restored has remained unknown. We show here that the DNA methyltransferase Dnmt3a interacts physically and functionally with TDG. Both the PWWP domain and the catalytic domain of Dnmt3a are able to mediate the interaction with TDG at its N-terminal. The interaction affects the enzymatic activity of both proteins: Dnmt3a positively regulates the glycosylase activity of TDG, while TDG inhibits the methylation activity of Dnmt3a. Dnmt3a also interacts with ligase III (a factor involved in base-excision repair). These data suggest a mechanistic link between DNA mismatch repair and re-methylation at sites affected by methylcytosine deamination. Coupling of the two processes may contribute to the stable maintenance of genomic methylation patterns in repair.
Keywords/Search Tags:DNA methyltransferase, DNA methylation, G/T mismatch repair, thymine DNA glycosylase
PDF Full Text Request
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