SWI/SNF Factors Required for Cellular Resistance to DNA Damage Include ARID1A and ARID1B and Show Interdependent Protein Stability
SWI/SNF Factors Required for Cellular Resistance to DNA Damage Include ARID1A and ARID1B and Show Interdependent Protein Stability
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DOI：
10.1158/0008-5472.can-13-3608
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发表时间：
2014-05-01
期刊：
影响因子：
11.2
通讯作者：
Yasui, Akira
中科院分区：
文献类型：
--
作者：
Watanabe, Reiko;Ui, Ayako;Yasui, Akira
SWI/SNF染色质重塑家族包含多种蛋白质复合物，其在细胞发育过程中调节基因表达，并以ATP和复合物依赖的方式影响DNA损伤反应，其中细节仍然难以捉摸。最近对各种癌细胞的人类基因组测序揭示了SWI/SNF因子中的频繁突变，特别是ARID 1A，SWI/SNF家族的BRG 1相关因子（BAF）复合物中的变体亚基。我们结合活细胞分析和基因抑制实验表明，抑制ARID 1A或其副产物ARID 1B导致DNA双链断裂（DSB）的非同源末端连接活性降低，DSB时KU 70/KU 80蛋白的积累减少，对电离辐射以及顺铂和UV的敏感性降低。因此，与转录调控相反，两种ARID 1蛋白都是细胞对各种类型的DNA损伤（包括DSB）的抗性所必需的。对其他SWI/SNF因子，即SNF 5、BAF 60 a、BAF 60 c、BAF 155或BAF 170的抑制表现出类似的表型。在这些因子中，ARID 1A、ARID 1B、SNF 5和BAF 60 c对于SWI/SNF复合物的ATP酶亚基向DSB的立即募集是必需的，认为这两种ARID 1蛋白促进复合物的损伤反应。最后，我们发现了SWI/SNF因子之间相互依赖的蛋白质稳定性，表明它们在复合物中的直接相互作用以及癌细胞中多个因子经常平行丢失的原因。综上所述，我们发现缺乏某些SWI/SNF因子（包括ARID 1A）表达的癌细胞缺乏DNA修复，可能容易受到DNA损伤。(C)2014年AACR。
The SWI/SNF chromatin-remodeling family contains various protein complexes, which regulate gene expression during cellular development and influence DNA damage response in an ATP-and complex-dependent manner, of which details remain elusive. Recent human genome sequencing of various cancer cells revealed frequent mutations in SWI/SNF factors, especially ARID1A, a variant subunit in the BRG1-associated factor (BAF) complex of the SWI/SNF family. We combined live-cell analysis and gene-suppression experiments to show that suppression of either ARID1A or its paralog ARID1B led to reduced nonhomologous end joining activity of DNA double-strand breaks (DSB), decreased accumulation of KU70/KU80 proteins at DSB, and sensitivity to ionizing radiation, as well as to cisplatin and UV. Thus, in contrast to transcriptional regulation, both ARID1 proteins are required for cellular resistance to various types of DNA damage, including DSB. The suppression of other SWI/SNF factors, namely SNF5, BAF60a, BAF60c, BAF155, or BAF170, exhibits a similar phenotype. Of these factors, ARID1A, ARID1B, SNF5, and BAF60c are necessary for the immediate recruitment of the ATPase subunit of the SWI/SNF complex to DSB, arguing that both ARID1 proteins facilitate the damage response of the complex. Finally, we found interdependent protein stability among the SWI/SNF factors, suggesting their direct interaction within the complex and the reason why multiple factors are frequently lost in parallel in cancer cells. Taken together, we show that cancer cells lacking in the expression of certain SWI/SNF factors, including ARID1A, are deficient in DNA repair and potentially vulnerable to DNA damage. (C) 2014 AACR.