title: MutS homologue hMSH5: role in cisplatin-induced DNA damage response.
abstract: BACKGROUND
  Cisplatin (cis-diamminedichloroplatinum (II), CDDP) and its analogues constitute an important class of anticancer drugs in the treatment of various malignancies; however, its effectiveness is frequently affected by mutations in genes involved in the repair and signaling of cisplatin-induced DNA damage. These observations necessitate a need for a better understanding of the molecular events governing cellular sensitivity to cisplatin.
  
  
  RESULTS
  Here, we show that hMSH5 mediates sensitization to cisplatin-induced DNA damage in human cells. Our study indicates that hMSH5 undergoes cisplatin-elicited protein induction and tyrosine phosphorylation. Silencing of hMSH5 by RNAi or expression of hMSH5 phosphorylation-resistant mutant hMSH5Y742F elevates cisplatin-induced G2 arrest and renders cells susceptible to cisplatin toxicity at clinically relevant doses. In addition, our data show that cisplatin promotes hMSH5 chromatin association and hMSH5 deficiency increases cisplatin-triggered γ-H2AX foci. Consistent with a possible role for hMSH5 in recombinational repair of cisplatin-triggered double-strand breaks (DSBs), the formation of cisplatin-induced hMSH5 nuclear foci is hRad51-dependent.
  
  
  CONCLUSIONS
  Collectively, our current study has suggested a role for hMSH5 in the processing of cisplatin-induced DSBs, and silencing of hMSH5 may provide a new means to improve the therapeutic efficacy of cisplatin.
authors.affiliation: School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Mail Drop 64-7520, Pullman, WA 99164, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Tompkins
authors.forename: Xiling
authors.initials: X
authors.lastname: Wu
authors.forename: Chengtao
authors.initials: C
authors.lastname: Her
mesh_terms: D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002945:Cisplatin / Q000009:adverse effects*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000187:drug effects*; D006801:Humans; D047468:Immunoprecipitation; D010766:Phosphorylation; D034622:RNA Interference
chemical_list: D018797:Cell Cycle Proteins; C118481:MSH5 protein, human; D002945:Cisplatin