TY - JOUR
T1 - USP13 regulates the RAP80-BRCA1 complex dependent DNA damage response
AU - Li, Yunhui
AU - Luo, Kuntian
AU - Yin, Yujiao
AU - Wu, Chenming
AU - Deng, Min
AU - Li, Lei
AU - Chen, Yuping
AU - Nowsheen, Somaira
AU - Lou, Zhenkun
AU - Yuan, Jian
N1 - Funding Information:
This work was supported by National Institutes of Health grant (CA203971 and CA203561), National Natural Science Foundation of China (81572770, 31371367, 81402286)
Publisher Copyright:
© Author(s) 2017.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms15752
DO - 10.1038/ncomms15752
M3 - Article
C2 - 28569838
AN - SCOPUS:85020043814
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
M1 - 15752
ER -