Molecular mechanism for USP7-mediated DNMT1 stabilization by acetylation

被引：120

作者：

Cheng, Jingdong ^{[1
,2
,3
]}

Yang, Huirong ^{[1
,2
,3
]}

Fang, Jian ^{[1
]}

Ma, Lixiang ^{[4
]}

Gong, Rui ^{[1
]}

Wang, Ping ^{[1
]}

Li, Ze ^{[1
]}

Xu, Yanhui ^{[1
,2
,3
]}

机构：

[1] Fudan Univ, Shanghai Med Coll, Sch Basic Med Sci, Shanghai Canc Ctr,Inst Biomed Sci, Shanghai 200032, Peoples R China

[2] Fudan Univ, Shanghai Med Coll, Sch Basic Med Sci, Dept Syst Biol Med,Key Lab Mol Med,Minist Educ, Shanghai 200032, Peoples R China

[3] Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, State Key Lab Genet Engn, Shanghai 200433, Peoples R China

[4] Fudan Univ, Shanghai Med Coll, Dept Anat & Histol & Embryol, Shanghai 200032, Peoples R China

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

基金：

中国国家自然科学基金;

关键词：

UBIQUITIN-SPECIFIC PROTEASE; DNA METHYLATION; PANCREATIC-CANCER; MAMMALIAN-CELLS; PRECLINICAL EVALUATION; GENE-EXPRESSION; GMP-SYNTHETASE; STABILITY; UHRF1; METHYLTRANSFERASE-1;

D O I：

10.1038/ncomms8023

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 angstrom 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.

引用

页数：11

共 51 条

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