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Genes Dev. 2016 Dec 1;30(23):2581-2595. doi: 10.1101/gad.289439.116. Epub 2016 Dec 9.

A phosphorylation-deubiquitination cascade regulates the BRCA2-RAD51 axis in homologous recombination.

Luo K1,2,3, Li L1,2, Li Y1,2, Wu C1,2, Yin Y1,2, Chen Y1,2, Deng M3, Nowsheen S4, Yuan J1,2,3, Lou Z3,5.

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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.
Medical Scientist Training Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic School of Medicine, Rochester, Minnesota 55905, USA.
Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.


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.


BRCA2; DNA damage response; Rad51; UCHL3; deubiquitination; homologous recombination

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