The epistatic relationship between BRCA2 and the other RAD51 mediators in homologous recombination.
The epistatic relationship between BRCA2 and the other RAD51 mediators in homologous recombination.
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DOI：
10.1371/journal.pgen.1002148
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发表时间：
2011-07
期刊：
影响因子：
4.5
通讯作者：
Takeda S
中科院分区：
文献类型：
--
作者：
Qing Y;Yamazoe M;Hirota K;Dejsuphong D;Sakai W;Yamamoto KN;Bishop DK;Wu X;Takeda S
RAD 51重组酶在双链断裂（DSB）位点聚合，在该处其执行DSB修复。RAD 51的缺失导致广泛的染色体断裂，导致细胞凋亡。RAD 51的聚合由许多RAD 51介体调节，例如BRCA 1、BRCA 2、RAD 52、SFR 1、SWS 1和五种RAD 51旁系同源物，包括XRCC 3。我们在这里发现，brca 2-null突变细胞能够增殖，表明RAD 51可以在没有BRCA 2的情况下进行DSB修复。我们破坏了brca 2缺失细胞中的BRCA 1、RAD 52、SFR 1、SWS 1和XRCC 3基因。所有产生的双突变细胞都显示出与brca 2缺失细胞非常相似的表型。因此，我们认为BRCA 2可以作为一个平台，在DNA损伤位点的适当位置招募各种RAD 51介质。BRCA 1和BRCA 2的突变易患遗传性乳腺癌和卵巢癌。这种突变对化疗药物敏感，包括喜树碱、顺铂和聚（ADP-核糖）聚合酶（PARP）抑制剂，因为包括两种BRCA蛋白的RAD 51介导剂促进这些药物诱导的DNA损伤的修复。很少有人知道的功能之间的关系RAD 51，BRCA 2，和其他RAD 51介质，因为没有brca 2空细胞。此外，sws 1突变体的表型尚未被记录。我们在此破坏了所有已知的RAD 51介体，并分析了BRCA 2缺陷和BRCA 2熟练背景下产生的突变体的表型。了解单个RAD 51介质的功能及其功能相互作用将有助于准确预测抗癌治疗效果。
RAD51 recombinase polymerizes at the site of double-strand breaks (DSBs) where it performs DSB repair. The loss of RAD51 causes extensive chromosomal breaks, leading to apoptosis. The polymerization of RAD51 is regulated by a number of RAD51 mediators, such as BRCA1, BRCA2, RAD52, SFR1, SWS1, and the five RAD51 paralogs, including XRCC3. We here show that brca2-null mutant cells were able to proliferate, indicating that RAD51 can perform DSB repair in the absence of BRCA2. We disrupted the BRCA1, RAD52, SFR1, SWS1, and XRCC3 genes in the brca2-null cells. All the resulting double-mutant cells displayed a phenotype that was very similar to that of the brca2-null cells. We suggest that BRCA2 might thus serve as a platform to recruit various RAD51 mediators at the appropriate position at the DNA–damage site. Mutations in BRCA1 and BRCA2 predispose hereditary breast and ovarian cancer. Such mutations sensitize to chemotherapeutic agents, including camptothecin, cisplatin, and poly(ADP-ribose) polymerase (PARP) inhibitor, since RAD51 mediators including both BRCA proteins promote repair of DNA lesions induced by these drugs. Little is known of the functional relationships among RAD51, BRCA2, and other RAD51 mediators, because no brca2-null cells were available. Furthermore, the phenotype of sws1 mutants has not been documented. We here disrupted every known RAD51 mediator and analyzed the phenotype of the resulting mutants in both BRCA2-deficient and -proficient backgrounds. The understanding of the function of individual RAD51 mediators and their functional interactions will contribute to the accurate prediction of anti-cancer therapy efficacy.
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DOI：
10.1056/nejmra0809889
发表时间：
2010-05-20
期刊：
The New England journal of medicine
影响因子：
--
作者：
D'Andrea AD
通讯作者：
D'Andrea AD
影响因子：
30.8
作者：
Connor, F;Bertwistle, D;Ashworth, A
通讯作者：
Ashworth, A
影响因子：
4.8
作者：
Fukushima, T;Takata, M;Takeda, S
通讯作者：
Takeda, S
影响因子：
16
作者：
Kawamoto, T;Araki, K;Takeda, S
通讯作者：
Takeda, S
影响因子：
4.8
作者：
Bhattacharyya, A;Ear, US;Bishop, DK
通讯作者：
Bishop, DK