USP13 regulates the RAP80-BRCA1 complex dependent DNA damage response.
USP13 regulates the RAP80-BRCA1 complex dependent DNA damage response.
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USP13 调节 RAP80-BRCA1 复合物依赖性 DNA 损伤反应
DOI：
10.1038/ncomms15752
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发表时间：
2017-06-01
影响因子：
16.6
通讯作者：
Yuan J
中科院分区：
文献类型：
--
作者：
Li Y;Luo K;Yin Y;Wu C;Deng M;Li L;Chen Y;Nowsheen S;Lou Z;Yuan J
BRCA1调节多种维持基因组稳定的细胞通路，包括细胞周期检查点、DNA修复、蛋白质泛素化、染色质重塑、转录调控和细胞凋亡。受体相关蛋白80(RAP80)通过支架蛋白CCDC98(Abraxas)帮助BRCA1招募双链断裂(DSB)，并促进DNA损伤反应(DDR)。然而，RAP80-BRCA1复合体的调控仍不清楚。在这里，我们报道了一种脱泛素酶，USP13，通过靶向RAP80来调节DDR。从机制上讲，USP13在DNA损伤后被ATM磷酸化，这反过来又促进了其DSB的定位。USP13反过来使RAP80去泛素化，并促进RAP80的招募和适当的DDR。耗尽或抑制USP13使卵巢癌细胞对顺铂和PARP抑制剂(Olaparib)敏感，而过表达USP13则使卵巢癌细胞对化疗产生抗药性。总体而言，我们认为USP13是DNA修复的调节因子，并揭示了一个模型，在该模型中，磷酸化-去泛素化轴动态调节RAP80-BRCA1复合灶的形成和功能。RAP80有助于招募BRCA1进行双链断裂，促进DNA损伤反应。在这里，作者报告说，在DNA损伤后，磷酸化的USP13去泛素化RAP80，促使募集到断裂位点。
BRCA1 regulates multiple cellular pathways that maintain genomic stability including cell cycle checkpoints, DNA repair, protein ubiquitination, chromatin remodelling, transcriptional regulation and apoptosis. Receptor-associated protein 80 (RAP80) helps recruit BRCA1 to double-strand breaks (DSBs) through the scaffold protein CCDC98 (Abraxas) and facilitates DNA damage response (DDR). However, the regulation of RAP80-BRCA1 complex is still unclear. Here we report that a deubiquitinase, USP13, regulates DDR by targeting RAP80. Mechanistically, USP13 is phosphorylated by ATM following DNA damage which, in turn, facilitates its DSB localization. USP13, in turn, deubiquitinates RAP80 and promotes RAP80 recruitment and proper DDR. Depleting or inhibiting USP13 sensitizes ovarian cancer cells to cisplatin and PARP inhibitor (olaparib) while overexpression of USP13 renders ovarian cancer cells resistant to chemotherapy. Overall, we identify USP13 as a regulator of DNA repair and reveal a model in which a phosphorylation-deubiquitination axis dynamically regulates RAP80-BRCA1 complex foci formation and function. RAP80 helps to recruit BRCA1 to double-strand breaks, facilitating DNA damage responses. Here the authors report that phosphorylated USP13 deubiquitinates RAP80 after DNA damage, prompting recruitment to the break site.