%0 Journal Article
%T MutS homologue hMSH5: role in cisplatin-induced DNA damage response
%A Joshua D Tompkins
%A Xiling Wu
%A Chengtao Her
%J Molecular Cancer
%D 2012
%I BioMed Central
%R 10.1186/1476-4598-11-10
%X 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 ¦Ã-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.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.Despite being members of the MMR protein family, the MSH5 homologues have not been demonstrated to function in MMR. Instead, studies in mice, C. elegans, and S. cerevisiae have shown that MSH5 plays an array of diverse functions ranging from meiotic recombinational DSB repair, maintenance of chromosome integrity, to DNA damage response [1-6]. Purified hMSH4-hMSH5 protein complexes have been shown to possess binding activities towards recombination intermediate structures including the Holliday junction [7], and endogenous hMSH5 has been shown to interact with a Holliday junction binding protein [8]. In addition, hMSH5 forms chromosomal foci in human fetal oocytes at different stages of meiotic prophase I [9].Coherent with a conjectured role in recombinational DSB repair, hMSH5 has been reported to interact with several proteins related to DSB sensing and repair, including the c-Abl tyrosine kinase and HR protein hRad51 [10,11]. It is observed that RAD51 silencing in MSH5-deficient C. elegans oocytes can result in chromosome fr
%K hMSH5
%K hMSH4
%K c-Abl
%K Cisplatin
%K Homologous recombination
%U http://www.molecular-cancer.com/content/11/1/10