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.
Highlights
BRCA1 regulates multiple cellular pathways that maintain genomic stability including cell cycle checkpoints, DNA repair, protein ubiquitination, chromatin remodelling, transcriptional regulation and apoptosis
We found that knockdown of USP13 dramatically decreased cisplatin-induced BRCA1 foci formation (Fig. 1a)
Receptor-associated protein 80 (RAP80) forms a complex with BRCA1, CCDC98 (Abraxas), BRCC36 and MERIT40, which was named BRCA1-A complex and plays an important role in DDR3,38
Summary
BRCA1 regulates multiple cellular pathways that maintain genomic stability including cell cycle checkpoints, DNA repair, protein ubiquitination, chromatin remodelling, transcriptional regulation and apoptosis. 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. BRCA1 functions in a number of cellular pathways that maintain genomic stability including DNA damage-induced cell cycle checkpoint activation, DNA repair, protein ubiquitination, chromatin remodelling, transcriptional regulation and apoptosis[10]. Previous studies suggested RAP80 is important for BRCA1 recruitment to the DSBs and RAP80 depletion results in loss of BRCA1 focus formation, induces genomic instability and impairs HR20–22. In response to DNA damage, USP13 is phosphorylated by ATM, which in turn facilitates USP13 recruitment to DSBs, RAP80 deubiquitination, and triggers DDR signalling. Depleting or inhibiting USP13 sensitizes ovarian cancer cells to cisplatin and Poly (ADPribose) polymerase (PARP) inhibitor (olaparib) suggesting USP13 is a potential novel therapeutic target for ovarian cancer
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
