MSH2 is a key DNA mismatch repair protein, which plays an important role in genomic stability. In addition to its DNA repair function, MSH2 serves as a sensor for DNA base analogs-provoked DNA replication errors and binds to various DNA damage-induced adducts to trigger cell cycle arrest or apoptosis. Loss or depletion of MSH2 from cells renders resistance to certain DNA-damaging agents. Therefore, the level of MSH2 determines DNA damage response. Previous studies showed that the level of MSH2 protein is modulated by the ubiquitin-proteasome pathway, and histone deacetylase 6 (HDAC6) serves as an ubiquitin E3 ligase. However, the deubiquitinating enzymes, which regulate MSH2 remain unknown. Here we report that ubiquitin-specific peptidase 10 (USP10) interacts with and stabilizes MSH2. USP10 deubiquitinates MSH2 in vitro and in vivo. Moreover, the protein level of MSH2 is positively correlated with the USP10 protein level in a panel of lung cancer cell lines. Knockdown of USP10 in lung cancer cells exhibits increased cell survival and decreased apoptosis upon the treatment of DNA-methylating agent N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) and antimetabolite 6-thioguanine (6-TG). The above phenotypes can be rescued by ectopic expression of MSH2. In addition, knockdown of MSH2 decreases the cellular mismatch repair activity. Overall, our results suggest a novel USP10-MSH2 pathway regulating DNA damage response and DNA mismatch repair.

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Published in Journal of Chemical Biology, v. 291, no. 20, p. 10783-10791.

This research was originally published in the Journal of Biological Chemistry. Zhang, M., Hu, C., Tong, D., Xiang, S., Williams, K., Bai, W., Li, G., Bepler, G., and Zhang, X. Ubiquitin-specific Peptidase 10 (USP10) Deubiquitinates and Stabilizes MutS Homolog 2 (MSH2) to Regulate Cellular Sensitivity to DNA Damage. J. Biol. Chem. 2016; 291: 10783-10791. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

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This work was supported in part by National Institutes of Health Grant R01CA164147, a New Investigator Grant 09KN-17 from Florida James and Esther King Biomedical Program, a Liz Tilberis award from Ovarian Cancer Research Fund, and the Karmanos Cancer Institute start-up funds (to X. Z.).