title: Ubiquitin-specific Peptidase 10 (USP10) Deubiquitinates and Stabilizes MutS Homolog 2 (MSH2) to Regulate Cellular Sensitivity to DNA Damage.
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 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.
authors.affiliation: From the Department of Pathology and Cell Biology, Morsani College of Medicine, Tampa, Florida 33612.
authors.forename: Mu
authors.initials: M
authors.lastname: Zhang
authors.affiliation: From the Department of Pathology and Cell Biology, Morsani College of Medicine, Tampa, Florida 33612.
authors.forename: Chen
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, Kentucky 40536.
authors.forename: Dan
authors.initials: D
authors.lastname: Tong
authors.affiliation: From the Department of Pathology and Cell Biology, Morsani College of Medicine, Tampa, Florida 33612.
authors.forename: Shengyan
authors.initials: S
authors.lastname: Xiang
authors.affiliation: From the Department of Pathology and Cell Biology, Morsani College of Medicine, Tampa, Florida 33612.
authors.forename: Kendra
authors.initials: K
authors.lastname: Williams
authors.affiliation: From the Department of Pathology and Cell Biology, Morsani College of Medicine, Tampa, Florida 33612, Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, and.
authors.forename: Wenlong
authors.initials: W
authors.lastname: Bai
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, Kentucky 40536.
authors.forename: Guo-Min
authors.initials: GM
authors.lastname: Li
authors.affiliation: Molecular Therapeutics Program, Karmanos Cancer Institute, Detroit, Michigan 48201.
authors.forename: Gerold
authors.initials: G
authors.lastname: Bepler
authors.affiliation: From the Department of Pathology and Cell Biology, Morsani College of Medicine, Tampa, Florida 33612, Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, and zhangx@karmanos.org.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhang
mesh_terms: D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D010447:Peptide Hydrolases / Q000235:genetics; D014452:Ubiquitins / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D014452:Ubiquitins; D010447:Peptide Hydrolases; D051718:MutS Homolog 2 Protein
keywords: DNA damage; DNA damage response; DNA repair; deubiquitylation (deubiquitination); ubiquitin