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Association of Dnmt3a and thymine DNA glycosylase links DNA methylation with base-excision repair

Biomedical Sciences Research Institute Computer Science Research Institute Environmental Sciences Research Institute Nanotechnology & Advanced Materials Research Institute

Li, Ya-Qiang, Zhou, Ping-Zhu, Zheng, Xiu-Dan, Walsh, Colum and Xu, Guo-Liang (2007) Association of Dnmt3a and thymine DNA glycosylase links DNA methylation with base-excision repair. NUCLEIC ACIDS RESEARCH, 35 (2). pp. 390-400. [Journal article]

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DOI: 10.1093/nar/gkl1052

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.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences
Faculty of Life and Health Sciences > School of Biomedical Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Molecular Medicine
Biomedical Sciences Research Institute > Molecular Medicine > Transcriptional Regulation & Epigenetics
ID Code:21709
Deposited By:Professor Colum Walsh
Deposited On:02 Apr 2012 10:56
Last Modified:11 Dec 2012 14:27

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