Ubiquitin-specific peptidase 10 (USP10) deubiquitinates and stabilizes MutS homolog 2 (MSH2) to regulate cellular sensitivity to DNA damage

Mu Zhang, Chen Hu, Dan Tong, Shengyan Xiang, Kendra Williams, Wenlong Bai, Guo Min Li, Gerold Bepler, Xiaohong Zhang

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

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 analogsprovoked 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 ofMSH2determines 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 deubiquitinatesMSH2in 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.

Original languageEnglish (US)
Pages (from-to)10783-10791
Number of pages9
JournalJournal of Biological Chemistry
Volume291
Issue number20
DOIs
StatePublished - May 13 2016

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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