BRCA1 and BRCA2 protect against oxidative DNA damage converted into double-strand breaks during DNA replication |
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| Institution: | 1. Department of Toxicology, Peking University Health Science Center, Beijing 100191, China;2. Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Peking University Health Science Center, Beijing 100191, China;3. Department of Toxicology, Shanghai Municipal Center for Disease Control & Prevention, Shanghai 200336, China;4. Chinese Academy of Inspection and Quarantine Comprehensive Test Center, Beijing 100123, China;5. Medical and Healthy Analytical Center, Peking University Health Science Center, Beijing 100191, China;6. Department of Toxicology, Faculty of Preventive Medicine, School of Public Health, Sun Yat-sen University, Guangzhou 510080, Guangdong, China;1. MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK;2. Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, BN1 9RQ, UK;1. Department of Microbiology and Immunology, Western University, London, Ontario, Canada;2. Cancer Research Laboratory Program, Lawson Health Research Institute, London, Ontario, Canada;3. Department of Oncology, Western University, London, Ontario, Canada;4. Department of Physiology and Pharmacology, Western University, London, Ontario, Canada;5. Department of Pathology, Western University, London, Ontario, Canada;1. Departamento de Andrología, Fundación Puigvert/Universidad Autónoma de Barcelona, Barcelona, Spain;2. Sección de Patología, Fundación Puigvert/Universidad Autónoma de Barcelona, Barcelona, Spain;3. Departamento de Patología, Hospital Clínico, Universidad de Chile, Santiago, Chile;4. Departamento de Urología, Hospital Clínico, Universidad de Chile, Santiago, Chile;5. Departamento de Urología, Clínica Las Condes, Santiago, Chile |
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| Abstract: | BRCA1 and BRCA2 mutation carriers are predisposed to develop breast and ovarian cancers, but the reasons for this tissue specificity are unknown. Breast epithelial cells are known to contain elevated levels of oxidative DNA damage, triggered by hormonally driven growth and its effect on cell metabolism. BRCA1- or BRCA2-deficient cells were found to be more sensitive to oxidative stress, modeled by treatment with patho-physiologic concentrations of hydrogen peroxide. Hydrogen peroxide exposure leads to oxidative DNA damage induced DNA double strand breaks (DSB) in BRCA-deficient cells causing them to accumulate in S-phase. In addition, after hydrogen peroxide treatment, BRCA deficient cells showed impaired Rad51 foci which are dependent on an intact BRCA1–BRCA2 pathway. These DSB resulted in an increase in chromatid-type aberrations, which are characteristic for BRCA1 and BRCA2-deficient cells. The most common result of oxidative DNA damage induced processing of S-phase DSB is an interstitial chromatid deletion, but insertions and exchanges were also seen in BRCA deficient cells. Thus, BRCA1 and BRCA2 are essential for the repair of oxidative DNA damage repair intermediates that persist into S-phase and produce DSB. The implication is that oxidative stress plays a role in the etiology of hereditary breast cancer. |
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| Keywords: | Cancer Oxidative stress Homologous recombination BRCA Chromosome aberrations |
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