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- Title
53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers.
- Authors
Bouwman, Peter; Aly, Amal; Escandell, Jose M.; Pieterse, Mark; Bartkova, Jirina; van der Gulden, Hanneke; Hiddingh, Sanne; Thanasoula, Maria; Kulkarni, Atul; Yang, Qifeng; Haffty, Bruce G.; Tommiska, Johanna; Blomqvist, Carl; Drapkin, Ronny; Adams, David J.; Nevanlinna, Heli; Bartek, Jiri; Tarsounas, Madalena; Ganesan, Shridar; Jonkers, Jos
- Abstract
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.
- Subjects
TRIPLE-negative breast cancer; GENETIC mutation; DNA repair; P53 protein; CARRIER proteins; PHOSPHOPROTEINS
- Publication
Nature Structural & Molecular Biology, 2010, Vol 17, Issue 6, p688
- ISSN
1545-9993
- Publication type
Article
- DOI
10.1038/nsmb.1831