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Molecular mechanism for USP7-mediated DNMT1 stabilization by acetylation

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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
    Key Laboratory of Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Shanghai Medical College of Fudan University
    State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University)

  • 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
    Key Laboratory of Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Shanghai Medical College of Fudan University
    State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University)

  • 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
    Key Laboratory of Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Shanghai Medical College of Fudan University
    State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University)

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.

Suggested Citation

  • Jingdong Cheng & Huirong Yang & Jian Fang & Lixiang Ma & Rui Gong & Ping Wang & Ze Li & Yanhui Xu, 2015. "Molecular mechanism for USP7-mediated DNMT1 stabilization by acetylation," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8023
    DOI: 10.1038/ncomms8023
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    Cited by:

    1. Yuan Liu & Dianke Li & Xin Zhang & Simin Xia & Yingjie Qu & Xinping Ling & Yang Li & Xiangren Kong & Lingqiang Zhang & Chun-Ping Cui & Dong Li, 2024. "A protein sequence-based deep transfer learning framework for identifying human proteome-wide deubiquitinase-substrate interactions," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Sandhya Malla & Kanchan Kumari & Carlos A. García-Prieto & Jonatan Caroli & Anna Nordin & Trinh T. T. Phan & Devi Prasad Bhattarai & Carlos Martinez-Gamero & Eshagh Dorafshan & Stephanie Stransky & Da, 2024. "The scaffolding function of LSD1 controls DNA methylation in mouse ESCs," Nature Communications, Nature, vol. 15(1), pages 1-24, December.

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