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Molecular mechanism for USP7-mediated DNMT1 stabilization by acetylation

Jingdong Cheng¹, Huirong Yang¹, Jian Fang²

¹1] 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.

Nature Communications

|May 12, 2015

Summary

DNA methyltransferase 1 (DNMT1) stability is regulated by its interaction with USP7. Acetylation disrupts this interaction, promoting DNMT1 degradation, which has implications for cancer therapy.

Area of Science:

Epigenetics
Structural Biology
Biochemistry

Background:

DNA methyltransferase 1 (DNMT1) is crucial for maintaining DNA methylation patterns.
USP7 is known to interact with and stabilize DNMT1.

Purpose of the Study:

To determine the crystal structure of the DNMT1-USP7 complex.
To elucidate the molecular mechanism of USP7-mediated DNMT1 stabilization.
To investigate the role of acetylation in regulating DNMT1 stability and its therapeutic potential.

Main Methods:

X-ray crystallography to determine the structure of the DNMT1-USP7 complex at 2.9 Å resolution.
Biochemical assays to study protein-protein interactions and acetylation.
Analysis of protein levels in differentiated neuronal and pancreatic cancer cells.

Main Results:

The crystal structure reveals that the DNMT1-USP7 interaction is mediated by USP7's acidic pocket and Lysine residues in DNMT1's KG linker.
Acetylation of these Lysine residues disrupts the DNMT1-USP7 interaction, leading to DNMT1 degradation.
HDAC inhibitor treatment increases DNMT1 acetylation and decreases total DNMT1 protein levels in relevant cell types.

Conclusions:

USP7 stabilizes DNMT1 through a specific structural interaction that is sensitive to acetylation.
Acetylation acts as a key regulatory switch for DNMT1 stability, impacting its levels in cancer cells.
The DNMT1-USP7 interaction surface presents a potential target for therapeutic intervention in epigenetic-related diseases.

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