Abstract
BackgroundCisplatin (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.ResultsHere, 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.ConclusionCollectively, 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.
Highlights
Cisplatin (cis-diamminedichloroplatinum (II), CDDP) and its analogues constitute an important class of anticancer drugs in the treatment of various malignancies; its effectiveness is frequently affected by mutations in genes involved in the repair and signaling of cisplatin-induced DNA damage
It is observed that RAD51 silencing in MutS homologue 5 (MSH5)-deficient C. elegans oocytes can result in chromosome fragmentation [6], suggesting that MSH5 and RAD51 may play a synergistic role in Double-strand break (DSB) processing at least during meiosis in C. elegans
It is well known that Homologous recombination (HR) is required for the resolution of cisplatin-induced DSBs [22,23,24], and most of the cisplatin-induced DSBs are created at replication forks during S phase [28]
Summary
Cisplatin (cis-diamminedichloroplatinum (II), CDDP) and its analogues constitute an important class of anticancer drugs in the treatment of various malignancies; its effectiveness is frequently affected by mutations in genes involved in the repair and signaling of cisplatin-induced DNA damage. Studies performed with mouse models and human patient samples have suggested a role for hMSH5 in class switch recombination during B and T cell development, whereas hMSH5 deficiency associates with long microhomologies at Ig switch joints [12]. These observations have raised the possibility that, through interacting with various DSB repair proteins, hMSH5 could exert multiple roles in DNA damage surveillance and DSB repair. In addition to its potential role in DNA repair, hMSH5
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