Molecular mechanism for USP7-mediated DNMT1 stabilization by acetylation

Jingdong Cheng, Huirong Yang, Jian Fang, Lixiang Ma, Rui Gong, Ping Wang, Ze Li and Yanhui Xu ()
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Jingdong Cheng: Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, 131 Dong An Road, Mingdao Building, Room 715, Shanghai 200032, China
Huirong Yang: Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, 131 Dong An Road, Mingdao Building, Room 715, Shanghai 200032, China
Jian Fang: Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, 131 Dong An Road, Mingdao Building, Room 715, Shanghai 200032, China
Lixiang Ma: Shanghai Medical College of Fudan University
Rui Gong: Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, 131 Dong An Road, Mingdao Building, Room 715, Shanghai 200032, China
Ping Wang: Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, 131 Dong An Road, Mingdao Building, Room 715, Shanghai 200032, China
Ze Li: Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, 131 Dong An Road, Mingdao Building, Room 715, Shanghai 200032, China
Yanhui Xu: Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, 131 Dong An Road, Mingdao Building, Room 715, Shanghai 200032, China

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms8023

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