ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors.
ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors.
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DOI：
10.1158/2159-8290.cd-14-0849
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发表时间：
2015-07
期刊：
影响因子：
28.2
通讯作者：
Peng G
中科院分区：
文献类型：
--
作者：
Shen J;Peng Y;Wei L;Zhang W;Yang L;Lan L;Kapoor P;Ju Z;Mo Q;Shih IeM;Uray IP;Wu X;Brown PH;Shen X;Mills GB;Peng G
ARID 1A是SWI/SNF家族的染色质重塑因子，是最近鉴定的肿瘤抑制因子，其在广谱人类癌症中突变。因此，了解其分子功能并确定ARID 1A缺陷是否可以用于治疗具有根本的临床重要性。在本文中，我们报告了ARID 1A在调节DNA损伤检查点中的关键功能。ARID 1A通过其与上游DNA损伤检查点激酶ATR的相互作用被募集到DNA双链断裂（DSB）。在分子水平上，ARID 1A促进DSB到单链末端的有效加工，并维持DNA损伤信号传导。重要的是，ARID 1A缺陷在体外和体内使癌细胞对PARP抑制剂敏感，为ARID 1A突变型肿瘤患者提供了潜在的治疗策略。
ARID1A, a chromatin remodeler of the SWI/SNF family, is a recently identified tumor suppressor that is mutated in a broad spectrum of human cancers. Thus, it is of fundamental clinical importance to understand its molecular functions and determine whether ARID1A deficiency can be exploited therapeutically. In this manuscript, we report a key function of ARID1A in regulating the DNA damage checkpoint. ARID1A is recruited to DNA double strand breaks (DSBs) via its interaction with the upstream DNA damage checkpoint kinase ATR. At the molecular level, ARID1A facilitates efficient processing of DSB to single strand ends, and sustains DNA damage signaling. Importantly, ARID1A deficiency sensitizes cancer cells to PARP inhibitors in vitro and in vivo providing a potential therapeutic strategy for patients with ARID1A-mutant tumors.