MutS homologue hMSH5: role in cisplatin-induced DNA damage response

Molecular Cancer

Research

Xiling Wu¹  Joshua D Tompkins¹  Chengtao Her¹ 

[1] School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Mail Drop 64-7520, 99164, Pullman, WA, USA;

关键词: hMSH5;    hMSH4;    c-Abl;    Cisplatin;    Homologous recombination;   

DOI  :  10.1186/1476-4598-11-10

 received in 2011-09-15, accepted in 2012-03-08,  发布年份 2012

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Tompkins et al; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.