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Nat Commun. 2017 Jun 1;8:15752. doi: 10.1038/ncomms15752.

USP13 regulates the RAP80-BRCA1 complex dependent DNA damage response.

Li Y1,2, Luo K1,2,3, Yin Y1,2, Wu C1,2, Deng M3, Li L1,2, Chen Y1,2, Nowsheen S4, Lou Z3, Yuan J1,2,3.

Author information

1
Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
2
Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
3
Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
4
Medical Scientist Training Program, Mayo Clinic School of Medicine, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, Minnesota 55905, USA.

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.

PMID:
28569838
PMCID:
PMC5461494
DOI:
10.1038/ncomms15752
[Indexed for MEDLINE]
Free PMC Article

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