USP13 regulates the RAP80-BRCA1 complex dependent DNA damage response

Yunhui Li, Kuntian Luo, Yujiao Yin, Chenming Wu, Min Deng, Lei Li, Yuping Chen, Somaira Nowsheen, Zhenkun Lou and Jian Yuan ()
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Yunhui Li: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine
Kuntian Luo: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine
Yujiao Yin: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine
Chenming Wu: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine
Min Deng: Mayo Clinic
Lei Li: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine
Yuping Chen: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine
Somaira Nowsheen: Medical Scientist Training Program, Mayo Clinic School of Medicine, Mayo Clinic Graduate School of Biomedical Sciences
Zhenkun Lou: Mayo Clinic
Jian Yuan: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms15752

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