title: A phosphorylation-deubiquitination cascade regulates the BRCA2-RAD51 axis in homologous recombination.
abstract: Homologous recombination (HR) is one of the major DNA double-strand break (DSB) repair pathways in mammalian cells. Defects in HR trigger genomic instability and result in cancer predisposition. The defining step of HR is homologous strand exchange directed by the protein RAD51, which is recruited to DSBs by BRCA2. However, the regulation of the BRCA2-RAD51 axis remains unclear. Here we report that ubiquitination of RAD51 hinders RAD51-BRCA2 interaction, while deubiquitination of RAD51 facilitates RAD51-BRCA2 binding and RAD51 recruitment and thus is critical for proper HR. Mechanistically, in response to DNA damage, the deubiquitinase UCHL3 is phosphorylated and activated by ATM. UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2. Overexpression of UCHL3 renders breast cancer cells resistant to radiation and chemotherapy, while depletion of UCHL3 sensitizes cells to these treatments, suggesting a determinant role of UCHL3 in cancer therapy. Overall, we identify UCHL3 as a novel regulator of DNA repair and reveal a model in which a phosphorylation-deubiquitination cascade dynamically regulates the BRCA2-RAD51 pathway.
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Kuntian
authors.initials: K
authors.lastname: Luo
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Li
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Chenming
authors.initials: C
authors.lastname: Wu
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Yujiao
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Deng
authors.affiliation: Medical Scientist Training Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic School of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Somaira
authors.initials: S
authors.lastname: Nowsheen
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.|Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lou
mesh_terms: D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D059765:Homologous Recombination / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D061986:MCF-7 Cells; D010766:Phosphorylation / Q000235:genetics; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011485:Protein Binding / Q000235:genetics; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D016019:Survival Analysis; D043222:Ubiquitin Thiolesterase; D054875:Ubiquitination / Q000187:drug effects / Q000235:genetics*
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051135:Rad51 Recombinase; C509806:UCHL3 protein, human; D043222:Ubiquitin Thiolesterase; D003546:Cysteine Endopeptidases
keywords: BRCA2; DNA damage response; Rad51; UCHL3; deubiquitination; homologous recombination