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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.

Original publication

DOI

10.1038/nsmb.1831

Type

Journal article

Journal

Nat Struct Mol Biol

Publication Date

06/2010

Volume

17

Pages

688 - 695

Keywords

Animals, Apoptosis Regulatory Proteins, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Cell Cycle, Cell Proliferation, Chromosomal Proteins, Non-Histone, DNA Damage, DNA Repair, DNA-Binding Proteins, Drug Resistance, Neoplasm, Embryonic Stem Cells, Female, Gene Deletion, Genes, BRCA1, Genes, BRCA2, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mice, Knockout, Mutagenesis, Insertional, Mutation, Tumor Cells, Cultured, Tumor Suppressor p53-Binding Protein 1