Molecular mechanism for USP7-mediated DNMT1 stabilization by acetylation.
Molecular mechanism for USP7-mediated DNMT1 stabilization by acetylation.
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USP7介导的乙酰化稳定DNMT1的分子机制
DOI：
10.1038/ncomms8023
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发表时间：
2015-05-11
影响因子：
16.6
通讯作者：
Xu, Yanhui
中科院分区：
文献类型：
--
作者：
Cheng, Jingdong;Yang, Huirong;Fang, Jian;Ma, Lixiang;Gong, Rui;Wang, Ping;Li, Ze;Xu, Yanhui
DNMT1是一种重要的表观遗传调控因子，在维持DNA甲基化过程中起着关键作用。在此，我们测定了DNMT1与USP7络合物的晶体结构，其分辨率为2.9 á。这两种蛋白质之间的相互作用主要是由USP7上的一个酸性口袋和DNMT1‘S KG接头上的赖氨酸残基介导的。这种分子间相互作用是USP7介导的DNMT1稳定所必需的。KG接头赖氨酸残基的乙酰化会削弱DNMT1-USP7的相互作用，促进DNMT1的降解。用HDAC抑制剂处理后，乙酰化的DNMT1增加，总DNMT1蛋白减少。在分化的神经细胞和胰腺癌细胞中观察到这种负相关。我们的研究揭示了USP7介导的DNMT1的稳定受乙酰化调节，并为抑制剂的设计提供了结构基础，靶向DNMT1-USP7相互作用表面用于治疗应用。DNMT1是一种甲基转移酶，参与维持组织特有的DNA甲基化模式。在这里，作者解决了DNMT1-USP7复合体的结构，并通过阻止与脱泛素酶USP7的结合，通过乙酰化来调节DNMT1的稳定性的机制。
DNMT1 is an important epigenetic regulator that plays a key role in the maintenance of DNA methylation. Here we determined the crystal structure of DNMT1 in complex with USP7 at 2.9 Å resolution. The interaction between the two proteins is primarily mediated by an acidic pocket in USP7 and Lysine residues within DNMT1's KG linker. This intermolecular interaction is required for USP7-mediated stabilization of DNMT1. Acetylation of the KG linker Lysine residues impair DNMT1–USP7 interaction and promote the degradation of DNMT1. Treatment with HDAC inhibitors results in an increase in acetylated DNMT1 and decreased total DNMT1 protein. This negative correlation is observed in differentiated neuronal cells and pancreatic cancer cells. Our studies reveal that USP7-mediated stabilization of DNMT1 is regulated by acetylation and provide a structural basis for the design of inhibitors, targeting the DNMT1–USP7 interaction surface for therapeutic applications. DNMT1 is a methyl-transferase involved in maintaining tissue-specific patterns of DNA methylation. Here the authors solve the structure of a DNMT1-USP7 complex and demonstrate the mechanism by which DNMT1 stability is regulated through acetylation by preventing association with the deubiquitinase USP7.
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影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
3.7
作者：
Han H;Yang X;Pandiyan K;Liang G
通讯作者：
Liang G
影响因子：
2.9
作者：
Deer EL;González-Hernández J;Coursen JD;Shea JE;Ngatia J;Scaife CL;Firpo MA;Mulvihill SJ
通讯作者：
Mulvihill SJ
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
16
作者：
Faesen, Alex C.;Dirac, Annette M. G.;Sixma, Titia K.
通讯作者：
Sixma, Titia K.