Association of Dnmt3a and thymine DNA glycosylase links DNA methylation with base-excision repair.
Association of Dnmt3a and thymine DNA glycosylase links DNA methylation with base-excision repair.
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DOI：
10.1093/nar/gkl1052
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发表时间：
2007
影响因子：
14.9
通讯作者：
Xu GL
中科院分区：
文献类型：
--
作者：
Li YQ;Zhou PZ;Zheng XD;Walsh CP;Xu GL
虽然甲基胞嘧啶作为编码表观遗传信息的第五个碱基，但由于其内在的不稳定性，它们也是危险的内源性诱变剂。甲基胞嘧啶以比胞嘧啶高得多的速率进行自发脱氨基作用以生成胸腺嘧啶。在哺乳动物中，两种修复酶，胸腺嘧啶DNA糖基化酶（TDG）和甲基-CpG结合结构域4（MBD 4），已经进化到抵消甲基胞嘧啶的诱变效应。两者都能识别甲基胞嘧啶脱氨引起的G/T错配，并启动碱基切除修复，将其纠正为G/C对。然而，修复的胞嘧啶的甲基化状态恢复的机制仍然未知。我们在这里表明，DNA甲基转移酶Dnmt 3a与TDG相互作用。Dnmt 3a的PWWP结构域和催化结构域都能够介导在其N-末端与TDG的相互作用。这种相互作用影响了两种蛋白的酶活性：Dnmt 3a在体外正调节TDG的糖基化酶活性，而TDG抑制Dnmt 3a的甲基化活性。这些数据表明，在甲基胞嘧啶脱氨基作用影响的位点，DNA修复和再甲基化之间存在机械联系。
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.
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影响因子：
56.9
作者：
Bourc'his, D;Xu, GL;Bestor, TH
通讯作者：
Bestor, TH
影响因子：
4
作者：
EHRLICH, M;NORRIS, KF;GEHRKE, CW
通讯作者：
GEHRKE, CW
影响因子：
3.5
作者：
Bestor, TH
通讯作者：
Bestor, TH
PWWP 结构域对从头 DNA 甲基转移酶的染色质靶向
影响因子：
4.8
作者：
Ge, YZ;Pu, MT;Xu, GL
通讯作者：
Xu, GL
影响因子：
11.4
作者：
Fuks, F;Burgers, WA;Kouzarides, T
通讯作者：
Kouzarides, T