Nucleic Acids Research Advance Access originally published online on December 14, 2006
Nucleic Acids Research 2007 35(2):390-400; doi:10.1093/nar/gkl1052
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Nucleic Acids Research, 2007, Vol. 35, No. 2 390-400
© 2006 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Nucleic Acid Enzymes |
Association of Dnmt3a and thymine DNA glycosylase links DNA methylation with base-excision repair
1 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 2 Graduate School of Chinese Academy of Sciences, 320 Yueyang Road Shanghai 200031, China 3 Centre for Molecular Biosciences, School of Biomedical Sciences University of Ulster BT52 1SA, Northern Ireland, UK
*To whom correspondence should be addressed. Tel: +86 21 5492 1332; Fax: +86 21 5492 1333; Email: glxu{at}sibs.ac.cn
Received June 2, 2006. Revised November 16, 2006. Accepted November 17, 2006.
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
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