53BP1 ablation rescues genomic instability in mice expressing ‘RING‐less’ BRCA1 |
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| Authors: | Minxing Li Francesca Cole Dharm S Patel Sarah M Misenko Joonyoung Her Amy Malhowski Ali Alhamza Haiyan Zheng Richard Baer Thomas Ludwig Maria Jasin André Nussenzweig Lourdes Serrano Samuel F Bunting |
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| Affiliation: | 1. Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, NJ, USA;2. Developmental Biology Program, Memorial Sloan‐Kettering Cancer Center, New York, NY, USA;3. Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA;4. Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;5. Biological Mass Spectrometry Facility, Rutgers, The State University of New Jersey, Piscataway, NJ, USA;6. Institute of Cancer Genetics, Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY, USA;7. Department of Cancer Biology & Genetics, Ohio State University, Columbus, OH, USA;8. Department of Genetics, Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, USA |
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| Abstract: | BRCA1 mutations strongly predispose affected individuals to breast and ovarian cancer, but the mechanism by which BRCA1 acts as a tumor suppressor is not fully understood. Homozygous deletion of exon 2 of the mouse Brca1 gene normally causes embryonic lethality, but we show that exon 2‐deleted alleles of Brca1 are expressed as a mutant isoform that lacks the N‐terminal RING domain. This “RING‐less” BRCA1 protein is stable and efficiently recruited to the sites of DNA damage. Surprisingly, robust RAD51 foci form in cells expressing RING‐less BRCA1 in response to DNA damage, but the cells nonetheless display the substantial genomic instability. Genomic instability can be rescued by the deletion of Trp53bp1, which encodes the DNA damage response factor 53BP1, and mice expressing RING‐less BRCA1 do not show an increased susceptibility to tumors in the absence of 53BP1. Genomic instability in cells expressing RING‐less BRCA1 correlates with the loss of BARD1 and a defect in restart of replication forks after hydroxyurea treatment, suggesting a role of BRCA1–BARD1 in genomic integrity that is independent of RAD51 loading. |
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| Keywords: | cancer DNA repair genomic integrity mouse models RAD51 |
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