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

16 Citations (Scopus)

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

Fingerprint

Ubiquitin
DNA Damage
Peptide Hydrolases
MutS Homolog 2 Protein
DNA Mismatch Repair
DNA
Repair
Cells
Lung Neoplasms
Apoptosis
Thioguanine
Methylnitronitrosoguanidine
Antimetabolites
Histone Deacetylases
Ubiquitin-Protein Ligases
Genomic Instability
Proteasome Endopeptidase Complex
Cell Cycle Checkpoints
DNA Replication
DNA Repair

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Ubiquitin-specific peptidase 10 (USP10) deubiquitinates and stabilizes MutS homolog 2 (MSH2) to regulate cellular sensitivity to DNA damage. / Zhang, Mu; Hu, Chen; Tong, Dan; Xiang, Shengyan; Williams, Kendra; Bai, Wenlong; Li, Guo Min; Bepler, Gerold; Zhang, Xiaohong.

In: Journal of Biological Chemistry, Vol. 291, No. 20, 13.05.2016, p. 10783-10791.

Research output: Contribution to journalArticle

Zhang, Mu ; Hu, Chen ; Tong, Dan ; Xiang, Shengyan ; Williams, Kendra ; Bai, Wenlong ; Li, Guo Min ; Bepler, Gerold ; Zhang, Xiaohong. / Ubiquitin-specific peptidase 10 (USP10) deubiquitinates and stabilizes MutS homolog 2 (MSH2) to regulate cellular sensitivity to DNA damage. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 20. pp. 10783-10791.
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