MutS homologue hMSH5: role in cisplatin-induced DNA damage response.
MutS homologue hMSH5: role in cisplatin-induced DNA damage response.
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DOI：
10.1186/1476-4598-11-10
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发表时间：
2012-03-08
期刊：
影响因子：
37.3
通讯作者：
Her C
中科院分区：
文献类型：
--
作者：
Tompkins JD;Wu X;Her C
顺铂(顺铂，CDDP)及其类似物是一类重要的抗癌药物，可用于多种恶性肿瘤的治疗，但其疗效往往受到参与顺铂所致DNA损伤修复和信号转导的基因突变的影响。这些观察结果需要更好地了解控制细胞对顺铂敏感性的分子事件。在这里，我们发现hMSH5介导了对顺铂诱导的人类细胞DNA损伤的敏化。我们的研究表明，hMSH5经历了顺铂诱导的蛋白诱导和酪氨酸磷酸化。RNAi沉默hMSH5或表达hMSH5磷酸化抗性突变体hMSH5Y742F可增加顺铂诱导的G2期停滞，并使细胞对临床相关剂量的顺铂毒性敏感。此外，我们的数据显示，顺铂促进了hMSH5染色质的结合，hMSH5缺乏增加了顺铂触发的γ-H2AX焦点。与hMSH5在顺铂触发的双链断裂(DSB)的重组修复中可能发挥的作用一致，顺铂诱导的hMSH5核灶的形成是hRad51依赖的。总之，我们目前的研究表明hMSH5在顺铂诱导的DSB的处理中发挥了作用，而沉默hMSH5可能为提高顺铂的治疗效果提供了一种新的手段。
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. 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. 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.
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影响因子：
3.8
作者：
Banáth JP;Klokov D;MacPhail SH;Banuelos CA;Olive PL
通讯作者：
Olive PL
影响因子：
3.1
作者：
Her, Chengtao;Zhao, Nianxi;Tompkins, Joshua D.
通讯作者：
Tompkins, Joshua D.
影响因子：
2.9
作者：
CICCARELLI, RB;SOLOMON, MJ;LIPPARD, SJ
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LIPPARD, SJ
影响因子：
2.6
作者：
Dolling, JA;Boreham, DR;Raaphorst, GP
通讯作者：
Raaphorst, GP
影响因子：
4.4
作者：
Her, C;Doggett, NA
通讯作者：
Doggett, NA