title: Molecular mechanism for USP7-mediated DNMT1 stabilization by acetylation.
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.
authors.affiliation: 1] 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 [2] Key Laboratory of Molecular Medicine, Ministry of Education, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China [3] State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Jingdong
authors.initials: J
authors.lastname: Cheng
authors.affiliation: 1] 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 [2] Key Laboratory of Molecular Medicine, Ministry of Education, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China [3] State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Huirong
authors.initials: H
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Jian
authors.initials: J
authors.lastname: Fang
authors.affiliation: Department of Anatomy and Histology &Embryology, Shanghai Medical College of Fudan University, Shanghai 200032, China.
authors.forename: Lixiang
authors.initials: L
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Rui
authors.initials: R
authors.lastname: Gong
authors.affiliation: 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.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Ze
authors.initials: Z
authors.lastname: Li
authors.affiliation: 1] 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 [2] Key Laboratory of Molecular Medicine, Ministry of Education, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China [3] State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D003460:Crystallization; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000076084:Ubiquitin-Specific Peptidase 7
chemical_list: C411744:DMAP1 protein, human; D012097:Repressor Proteins; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7