Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 17, Issue 6, Pages 688-U56Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.1831
Keywords
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Funding
- Dutch Cancer Society
- Netherlands Organization for Scientific Research
- European Community
- Cancer Research UK
- Breast Cancer Campaign
- US Department of Defense
- US National Cancer Institute
- Sidney Kimmel Foundation
- Breast Cancer Research Foundation
- Danish Cancer Society
- Danish National Research Foundation
- Vilhelm Pedersen and Hustrus Mindelegat
- Czech Ministry of Education
- Helsinki University Central Hospital Research Fund
- Finnish Cancer Society
- Academy of Finland [132473]
- Sigrid Juselius Foundation
- Wellcome Trust
- Academy of Finland (AKA) [132473, 132473] Funding Source: Academy of Finland (AKA)
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Germ-line mutations in breast cancer 1, early onset (BRCA1) result in predisposition to breast and ovarian cancer. BRCA1-mutated tumors show genomic instability, mainly as a consequence of impaired recombinatorial DNA repair. Here we identify p53-binding protein 1 (53BP1) as an essential factor for sustaining the growth arrest induced by Brca1 deletion. Depletion of 53BP1 abrogates the ATM-dependent checkpoint response and G2 cell-cycle arrest triggered by the accumulation of DNA breaks in Brca1-deleted cells. This effect of 53BP1 is specific to BRCA1 function, as 53BP1 depletion did not alleviate proliferation arrest or checkpoint responses in Brca2-deleted cells. Notably, loss of 53BP1 partially restores the homologous-recombination defect of Brca1-deleted cells and reverts their hypersensitivity to DNA-damaging agents. We find reduced 53BP1 expression in subsets of sporadic triple-negative and BRCA-associated breast cancers, indicating the potential clinical implications of our findings.
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