title: Association of Dnmt3a and thymine DNA glycosylase links DNA methylation with base-excision repair.
abstract: 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 repair enzymes, thymine DNA glycosylase (TDG) and methyl-CpG binding domain 4 (MBD4), 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 with TDG. Both the PWWP domain and the catalytic domain of Dnmt3a are able to mediate the interaction with TDG at its N-terminus. 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 in vitro. These data suggest a mechanistic link between DNA repair and remethylation at sites affected by methylcytosine deamination.
authors.affiliation: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Ya-Qiang
authors.initials: YQ
authors.lastname: Li
authors.forename: Ping-Zhu
authors.initials: PZ
authors.lastname: Zhou
authors.forename: Xiu-Dan
authors.initials: XD
authors.lastname: Zheng
authors.forename: Colum P
authors.initials: CP
authors.lastname: Walsh
authors.forename: Guo-Liang
authors.initials: GL
authors.lastname: Xu
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004260:DNA Repair; D006801:Humans; D051379:Mice; D017434:Protein Structure, Tertiary; D044502:Thymine DNA Glycosylase / Q000737:chemistry / Q000378:metabolism*
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D044502:Thymine DNA Glycosylase