BRG1 promotes the repair of DNA double-strand breaks by facilitating the replacement of RPA with RAD51
BRG1 promotes the repair of DNA double-strand breaks by facilitating the replacement of RPA with RAD51
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BRG1通过促进RAD51替换RPA来促进DNA双链断裂的修复
DOI：
10.1242/jcs.159103
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发表时间：
2015-01-15
影响因子：
4
通讯作者：
Zeng, Xianlu
中科院分区：
文献类型：
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作者：
Qi, Wenjing;Wang, Ruoxi;Zeng, Xianlu
摘要DNA双链断裂（DSB）是一种致死性的DNA损伤。DSB的修复需要调节染色质结构的因子与DNA修复机制之间的紧密协调。BRG 1是染色质重塑复合物Switch/Sucrose non-fermentable（SWI/SNF）的ATP酶亚基，通常与肿瘤发生和基因组不稳定性有关，其在DSB修复中的作用在很大程度上仍不清楚。在本研究中，我们发现BRG 1被募集到DSB位点并增强DSB修复。使用DR-GFP和EJ 5-GFP报告系统，我们证明，BRG 1促进同源重组修复，而不是非同源末端连接（NHEJ）修复。此外，BRG 1-RAD 52复合物介导单链DNA（ssDNA）上的RAD 51对RPA的替换以启动DNA链侵入。BRG 1的缺失导致RAD 51加载到ssDNA上失败、异常同源重组修复和增强DSB诱导的致死性。我们目前的研究提供了一个机制的洞察BRG 1，这是已知的参与染色质重塑，在哺乳动物细胞的同源重组修复途径中发挥了重要作用。
ABSTRACT DNA double-strand breaks (DSBs) are a type of lethal DNA damage. The repair of DSBs requires tight coordination between the factors modulating chromatin structure and the DNA repair machinery. BRG1, the ATPase subunit of the chromatin remodelling complex Switch/Sucrose non-fermentable (SWI/SNF), is often linked to tumorigenesis and genome instability, and its role in DSB repair remains largely unclear. In the present study, we show that BRG1 is recruited to DSB sites and enhances DSB repair. Using DR-GFP and EJ5-GFP reporter systems, we demonstrate that BRG1 facilitates homologous recombination repair rather than nonhomologous end-joining (NHEJ) repair. Moreover, the BRG1–RAD52 complex mediates the replacement of RPA with RAD51 on single-stranded DNA (ssDNA) to initiate DNA strand invasion. Loss of BRG1 results in a failure of RAD51 loading onto ssDNA, abnormal homologous recombination repair and enhanced DSB-induced lethality. Our present study provides a mechanistic insight into how BRG1, which is known to be involved in chromatin remodelling, plays a substantial role in the homologous recombination repair pathway in mammalian cells.