title: MutS homologue hMSH5: recombinational DSB repair and non-synonymous polymorphic variants.
abstract: Double-strand breaks (DSBs) constitute the most deleterious form of DNA lesions that can lead to genome alterations and cell death, and the vast majority of DSBs arise pathologically in response to DNA damaging agents such as ionizing radiation (IR) and chemotherapeutic agents. Recent studies have implicated a role for the human MutS homologue hMSH5 in homologous recombination (HR)-mediated DSB repair and the DNA damage response. In the present study, we show that hMSH5 promotes HR-based DSB repair, and this property resides in the carboxyl-terminal portion of the protein. Our results demonstrate that DSB-triggered hMSH5 chromatin association peaks at the proximal regions of the DSB and decreases gradually with increased distance from the break. Furthermore, the DSB-triggered hMSH5 chromatin association is preceded by and relies on the assembly of hMRE11 and hRad51 at the proximal regions of the DSB. Lastly, the potential effects of hMSH5 non-synonymous variants (L85F, Y202C, V206F, R351G, L377F, and P786S) on HR and cell survival in response to DSB-inducing anticancer agents have been analyzed. These experiments show that the expression of hMSH5 variants elicits different survival responses to anticancer drugs cisplatin, bleomycin, doxorubicin and camptothecin. However, the effects of hMSH5 variants on survival responses to DSB-inducing agents are not directly correlated to their effects exerted on HR-mediated DSB repair, suggesting that the roles of hMSH5 variants in the processes of DNA damage response and repair are multifaceted.
authors.affiliation: School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, Washington, United States of America.
authors.forename: Xiling
authors.initials: X
authors.lastname: Wu
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Katey
authors.initials: K
authors.lastname: Feng
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Tompkins
authors.forename: Chengtao
authors.initials: C
authors.lastname: Her
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002843:Chromatin / Q000187:drug effects / Q000235:genetics; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D059765:Homologous Recombination / Q000187:drug effects; D006801:Humans; D000076228:MRE11 Homologue Protein; D009154:Mutation; D011110:Polymorphism, Genetic; D051135:Rad51 Recombinase / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C118481:MSH5 protein, human; D051135:Rad51 Recombinase; D000076228:MRE11 Homologue Protein
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