Poly(ADP-Ribose) Mediates the BRCA2-Dependent Early DNA Damage Response.
Poly(ADP-Ribose) Mediates the BRCA2-Dependent Early DNA Damage Response.
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Poly(ADP-Ribose) 介导 BRCA2 依赖性早期 DNA 损伤反应
DOI：
10.1016/j.celrep.2015.09.040
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发表时间：
2015-10-27
期刊：
影响因子：
8.8
通讯作者：
Yu X
中科院分区：
文献类型：
--
作者：
Zhang F;Shi J;Bian C;Yu X
乳腺癌易感基因2（BRCA 2）在DNA损伤修复中起着关键作用，以维持基因组的稳定性。先前的研究表明，BRCA 2包含三个串联的寡核苷酸/寡糖结合折叠（OB-折叠），它们在DNA双链断裂修复过程中参与DNA结合。然而，BRCA 2在DNA损伤修复中的分子机制仍然是难以捉摸的。出乎意料的是，我们发现BRCA 2的OB-折叠识别聚（ADP-核糖）（PAR）并介导BRCA 2向DNA损伤的快速募集，这被PARP抑制剂治疗抑制。BRCA 2 OB折叠中的癌症相关突变破坏了与PAR的相互作用，并消除了BRCA 2快速重新定位到DNA损伤。快速募集的BRCA 2对于核酸外切酶1（EXO 1）的早期募集很重要，并参与DNA末端切除，这是同源重组（HR）的第一步。因此，这些发现揭示了BRCA 2参与DNA损伤修复的分子机制。Zhang等人表明，BRCA 2 OB-折叠作为聚（ADP-核糖）结合模块，介导BRCA 2快速募集至DNA损伤。BRCA 2的早期募集对于EXO 1依赖性DNA末端切除是重要的，这是同源重组（HR）修复的初始步骤。
Breast Cancer Susceptibility Gene 2 (BRCA2) plays a key role in DNA damage repair for maintaining genomic stability. Previous studies have shown that BRCA2 contains three tandem oligonucleotide/oligosaccharide binding folds (OB-folds) that are involved in DNA-binding during DNA double-strand break repair. However, the molecular mechanism of BRCA2 in DNA damage repair remains elusive. Unexpectedly, we found that the OB-folds of BRCA2 recognize poly(ADP-ribose) (PAR) and mediate the fast recruitment of BRCA2 to DNA lesions, which is suppressed by PARP inhibitor treatment. Cancer-associated mutations in the OB-folds of BRCA2 disrupt the interaction with PAR and abolish the fast relocation of BRCA2 to DNA lesions. The quickly recruited BRCA2 is important for the early recruitment of exonuclease 1(EXO1) and is involved in DNA end resection, the first step of homologous recombination (HR). Thus, these findings uncover a molecular mechanism by which BRCA2 participates in DNA damage repair. Zhang et al. show that BRCA2 OB-folds act as a poly(ADP-ribose)-binding module and mediate the fast recruitment of BRCA2 to DNA lesions. The early recruitment of BRCA2 is important for EXO1-dependent DNA end resection, the initial step of homologous recombination (HR) repair.