Functional and mutational landscapes of BRCA1 for homology-directed repair and therapy resistance
Functional and mutational landscapes of BRCA1 for homology-directed repair and therapy resistance
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DOI：
10.7554/elife.21350
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发表时间：
2017-04-11
期刊：
影响因子：
7.7
通讯作者：
Xia, Bing
中科院分区：
文献类型：
--
作者：
Anantha, Rachel W.;Simhadri, Srilatha;Xia, Bing
BRCA 1在DNA双链断裂的同源定向修复（HDR）中起着关键作用，而BRCA 1突变癌细胞的修复缺陷正被铂类药物和聚（ADP-核糖）聚合酶（PARP）抑制剂所靶向。我们采用相对简单且灵敏的测定方法来确定BRCA 1变体或突变体在两种HDR机制（同源重组（HR）和单链退火（SSA））中的功能，以及在赋予人类癌细胞对顺铂和奥拉帕尼耐药性方面的功能。我们的研究结果定义了前22位患者来源的BRCA 1错义变体的功能，以及BRCA 1的不同结构域及其E3泛素连接酶活性对HDR和耐药性的贡献。重要的是，我们的研究结果还表明，BRCA 1-PALB 2相互作用决定了HR和SSA之间的选择。这些研究建立了BRCA 1对HDR和治疗抗性的功能和突变景观，同时揭示了对BRCA 1调节机制和HDR途径选择的新见解。
BRCA1 plays a critical role in homology-directed repair (HDR) of DNA double strand breaks, and the repair defect of BRCA1-mutant cancer cells is being targeted with platinum drugs and poly (ADP-ribose) polymerase (PARP) inhibitors. We have employed relatively simple and sensitive assays to determine the function of BRCA1 variants or mutants in two HDR mechanisms, homologous recombination (HR) and single strand annealing (SSA), and in conferring resistance to cisplatin and olaparib in human cancer cells. Our results define the functionality of the top 22 patient-derived BRCA1 missense variants and the contribution of different domains of BRCA1 and its E3 ubiquitin ligase activity to HDR and drug resistance. Importantly, our results also demonstrate that the BRCA1-PALB2 interaction dictates the choice between HR and SSA. These studies establish functional and mutational landscapes of BRCA1 for HDR and therapy resistance, while revealing novel insights into BRCA1 regulatory mechanisms and HDR pathway choice.