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

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          Abstract

          In this study, Luo et al. investigated the regulation of the BRCA2–RAD51 axis in homologous recombination (HR) during DNA double-strand break (DSB) repair. The authors identify UCHL3 as a novel regulator of DNA repair and propose a model in which a phosphorylation–deubiquitination cascade dynamically regulates the BRCA2–RAD51 pathway.

          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.

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          The DNA-damage response in human biology and disease.

          The prime objective for every life form is to deliver its genetic material, intact and unchanged, to the next generation. This must be achieved despite constant assaults by endogenous and environmental agents on the DNA. To counter this threat, life has evolved several systems to detect DNA damage, signal its presence and mediate its repair. Such responses, which have an impact on a wide range of cellular events, are biologically significant because they prevent diverse human diseases. Our improving understanding of DNA-damage responses is providing new avenues for disease management.
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            Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.

            BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination, and mutations in these genes predispose to breast and other cancers. Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. We show here that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer.
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              Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.

              Poly(ADP-ribose) polymerase (PARP1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Nevertheless, PARP1-/- mice are viable, fertile and do not develop early onset tumours. Here, we show that PARP inhibitors trigger gamma-H2AX and RAD51 foci formation. We propose that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair. Furthermore, we show that BRCA2-deficient cells, as a result of their deficiency in homologous recombination, are acutely sensitive to PARP inhibitors, presumably because resultant collapsed replication forks are no longer repaired. Thus, PARP1 activity is essential in homologous recombination-deficient BRCA2 mutant cells. We exploit this requirement in order to kill BRCA2-deficient tumours by PARP inhibition alone. Treatment with PARP inhibitors is likely to be highly tumour specific, because only the tumours (which are BRCA2-/-) in BRCA2+/- patients are defective in homologous recombination. The use of an inhibitor of a DNA repair enzyme alone to selectively kill a tumour, in the absence of an exogenous DNA-damaging agent, represents a new concept in cancer treatment.
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                Author and article information

                Journal
                Genes Dev
                Genes Dev
                genesdev
                genesdev
                GAD
                Genes & Development
                Cold Spring Harbor Laboratory Press
                0890-9369
                1549-5477
                1 December 2016
                : 30
                : 23
                : 2581-2595
                Affiliations
                [1 ]Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China;
                [2 ]Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China;
                [3 ]Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA;
                [4 ]Medical Scientist Training Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic School of Medicine, Rochester, Minnesota 55905, USA;
                [5 ]Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China
                Author notes
                [6]

                These authors contributed equally to this work.

                Article
                8711660
                10.1101/gad.289439.116
                5204351
                27941124
                3b5827ef-6a74-481e-9390-4c99cd0424ad
                © 2016 Luo et al.; Published by Cold Spring Harbor Laboratory Press

                This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 18 August 2016
                : 30 November 2016
                Page count
                Pages: 15
                Funding
                Funded by: National Basic Research Program of China
                Award ID: 2013CB530700
                Funded by: International S&T Cooperation Program of China
                Award ID: 2015DFA30610
                Funded by: National Natural Science Foundation of China http://dx.doi.org/10.13039/501100001809
                Award ID: 31270806
                Award ID: 81322031
                Award ID: 81572770
                Award ID: 31371367
                Funded by: National Institutes of Health http://dx.doi.org/10.13039/100000002
                Award ID: CA203971
                Award ID: CA130996
                Award ID: CA189666
                Award ID: CA203561
                Funded by: Mayo Clinic http://dx.doi.org/10.13039/100000871
                Award ID: P50CA136393
                Funded by: Mayo Clinic http://dx.doi.org/10.13039/100000871
                Award ID: P50CA116201
                Funded by: Mayo Clinic http://dx.doi.org/10.13039/100000871
                Categories
                Research Paper

                brca2,dna damage response,homologous recombination,rad51,uchl3,deubiquitination

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