USP13 regulates the RAP80-BRCA1 complex dependent DNA damage response

• Published in: Nature communications 2017-06, Vol.8 (1), p.15752-15752, Article 15752
• Main Authors: Li, Yunhui, Luo, Kuntian, Yin, Yujiao, Wu, Chenming, Deng, Min, Li, Lei, Chen, Yuping, Nowsheen, Somaira, Lou, Zhenkun, Yuan, Jian
• Format: Article
• Language: English
• Subjects: 631/337/1427/2122; 631/80/458/582; Animals; Ataxia Telangiectasia Mutated Proteins - metabolism; BRCA1 Protein - genetics; BRCA1 Protein - metabolism; Cancer therapies; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell cycle; Cell Line, Tumor; Cisplatin - pharmacology; DNA damage; DNA repair; DNA Repair - physiology; DNA-Binding Proteins; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Endopeptidases - genetics; Endopeptidases - metabolism; Female; Histone Chaperones; Humanities and Social Sciences; Humans; Medicine; Mice, Nude; multidisciplinary; Multiprotein Complexes - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Phosphorylation; Phthalazines - pharmacology; Piperazines - pharmacology; Proteins; Recruitment; Science; Science (multidisciplinary); Signal transduction; Ubiquitination; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms15752

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.