PARP-1-dependent recruitment of cold-inducible RNA-binding protein promotes double-strand break repair and genome stability
PARP-1-dependent recruitment of cold-inducible RNA-binding protein promotes double-strand break repair and genome stability
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DOI：
10.1073/pnas.1713912115
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发表时间：
2018-02-20
影响因子：
11.1
通讯作者：
Liu, Hung-wen
中科院分区：
文献类型：
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作者：
Chen, Jung-Kuei;Lin, Wen-Ling;Liu, Hung-wen
维持基因组的完整性对于遗传信息的忠实传播和防止各种DNA损伤事件引起的突变至关重要。在这里，我们报道了冷诱导rna结合蛋白（CIRBP）是DNA双链断裂（DSB）修复中新发现的关键调节因子。在DNA损伤时，CIRBP在受损区域暂时积累，并被聚（ADP核糖）聚合酶-1 （PARP-1）聚合成聚（ADP核糖）核糖基。它与损伤部位的分离可能取决于磷脂酰肌醇3激酶相关激酶介导的磷酸化状态。在没有CIRBP的情况下，细胞显示H2AX、Rad51和53BP1灶形成减少。此外，CIRBP缺失的细胞表现出同源重组受损，非同源端连接受损，微核形成增加，对伽马辐射的敏感性更高，表明CIRBP积极参与DSB修复。此外，CIRBP缺失的细胞在DNA损伤诱导的MRN复合物（Mre11、Rad50和NBS1）和ATM激酶的染色质关联中表现出缺陷。CIRBP缺失也降低了多种ATM底物蛋白的磷酸化，从而削弱了DNA损伤反应。综上所述，这些结果揭示了CIRBP在DSB修复中的先前未被认识到的作用。
Maintenance of genome integrity is critical for both faithful propagation of genetic information and prevention of mutagenesis induced by various DNA damage events. Here we report cold-inducible RNA-binding protein (CIRBP) as a newly identified key regulator in DNA double-strand break (DSB) repair. On DNA damage, CIRBP temporarily accumulates at the damaged regions and is poly(ADP ribosyl) ated by poly(ADP ribose) polymerase-1 (PARP-1). Its dissociation from the sites of damage may depend on its phosphorylation status as mediated by phosphatidylinositol 3-kinase-related kinases. In the absence of CIRBP, cells showed reduced gamma H2AX, Rad51, and 53BP1 foci formation. Moreover, CIRBP-depleted cells exhibited impaired homologous recombination, impaired nonhomologous endjoining, increased micronuclei formation, and higher sensitivity to gamma irradiation, demonstrating the active involvement of CIRBP in DSB repair. Furthermore, CIRBP depleted cells exhibited defects in DNA damage-induced chromatin association of the MRN complex (Mre11, Rad50, and NBS1) and ATM kinase. CIRBP depletion also reduced phosphorylation of a variety of ATM substrate proteins and thus impaired the DNA damage response. Taken together, these results reveal a previously unrecognized role for CIRBP in DSB repair.