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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Ataxia Telangiectasia Mutated Proteins / metabolism
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BRCA1 Protein / genetics
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BRCA1 Protein / metabolism*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line, Tumor
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Cisplatin / pharmacology
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DNA Repair / physiology
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DNA-Binding Proteins
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics
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Endopeptidases / genetics
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Endopeptidases / metabolism*
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Female
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Histone Chaperones
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Humans
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Mice, Nude
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Multiprotein Complexes / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Ovarian Neoplasms / drug therapy
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / pathology
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Phosphorylation
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Phthalazines / pharmacology
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Piperazines / pharmacology
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Ubiquitin-Specific Proteases
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Ubiquitination
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Xenograft Model Antitumor Assays
Substances
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BRCA1 Protein
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BRCA1 protein, human
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Carrier Proteins
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DNA-Binding Proteins
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Histone Chaperones
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Multiprotein Complexes
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Nuclear Proteins
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Phthalazines
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Piperazines
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UIMC1 protein, human
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Endopeptidases
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USP13 protein, human
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Ubiquitin-Specific Proteases
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Cisplatin
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olaparib