Downregulation of SWI/SNF chromatin remodeling factor subunits modulates cisplatin cytotoxicity
Downregulation of SWI/SNF chromatin remodeling factor subunits modulates cisplatin cytotoxicity
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DOI：
10.1016/j.yexcr.2012.06.011
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发表时间：
2012-10-01
影响因子：
3.7
通讯作者：
Patrick, Steve M.
中科院分区：
文献类型：
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作者：
Kothandapani, Anbarasi;Gopalakrishnan, Kathirvel;Patrick, Steve M.
染色质重塑复合物SWI/SNF在转录、增殖、分化和DNA修复等细胞过程中起重要作用。在这份报告中，我们研究了SWI/SNF催化亚基Brg 1和Brm在肺癌和头颈癌细胞对顺铂的细胞反应中的作用。稳定敲除Brg 1和Brm增强细胞对顺铂的敏感性。顺铂DNA加合物的修复动力学表明，下调Brg 1和Brm阻碍了链内加合物和链间交联（ICLs）的修复。在Brg 1和Brm缺失的细胞中，顺铂ICL诱导的DNA双链断裂修复也减少。在Brg 1和Brm缺陷细胞中观察到检查点激活改变，细胞凋亡增强以及染色质松弛受损。Brg 1和Brm的下调并不影响DNA损伤识别因子XPC对顺铂DNA损伤的募集，但影响ERCC 1的募集，ERCC 1参与DNA修复的后期阶段。基于这些结果，我们提出SWI/SNF染色质重塑复合物通过促进顺铂DNA损伤的有效修复来调节顺铂的细胞毒性。(C)2012 Elsevier Inc. All rights reserved.
Chromatin remodeling complex SWI/SNF plays important roles in many cellular processes including transcription, proliferation, differentiation and DNA repair. In this report, we investigated the role of SWI/SNF catalytic subunits Brg1 and Brm in the cellular response to cisplatin in lung cancer and head/neck cancer cells. Stable knockdown of Brg1 and Brm enhanced cellular sensitivity to cisplatin. Repair kinetics of cisplatin DNA adducts revealed that downregulation of Brg1 and Brm impeded the repair of both intrastrand adducts and interstrand crosslinks (ICLs). Cisplatin ICL-induced DNA double strand break repair was also decreased in Brg1 and Brm depleted cells. Altered checkpoint activation with enhanced apoptosis as well as impaired chromatin relaxation was observed in Brg1 and Brm deficient cells. Downregulation of Brg1 and Brm did not affect the recruitment of DNA damage recognition factor XPC to cisplatin DNA lesions, but affected ERCC1 recruitment, which is involved in the later stages of DNA repair. Based on these results, we propose that SWI/SNF chromatin remodeling complex modulates cisplatin cytotoxicity by facilitating efficient repair of the cisplatin DNA lesions. (C) 2012 Elsevier Inc. All rights reserved.