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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Comment
MeSH terms
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Animals
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Apoptosis Regulatory Proteins
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BRCA1 Protein / deficiency*
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BRCA1 Protein / genetics*
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BRCA2 Protein / deficiency
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BRCA2 Protein / genetics
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics*
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cell Cycle
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Cell Proliferation
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Chromosomal Proteins, Non-Histone
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DNA Damage
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DNA Repair
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DNA-Binding Proteins
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Drug Resistance, Neoplasm / genetics
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Drug Resistance, Neoplasm / physiology
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Embryonic Stem Cells / cytology
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Embryonic Stem Cells / metabolism
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Female
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Gene Deletion
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Genes, BRCA1*
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Genes, BRCA2
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Intracellular Signaling Peptides and Proteins / deficiency
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Intracellular Signaling Peptides and Proteins / genetics
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Mice
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Mice, Knockout
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Mutagenesis, Insertional
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Mutation*
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Tumor Cells, Cultured
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Tumor Suppressor p53-Binding Protein 1
Substances
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Apoptosis Regulatory Proteins
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BLID protein, human
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BRCA1 Protein
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BRCA1 protein, human
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BRCA2 Protein
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BRCA2 protein, human
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Chromosomal Proteins, Non-Histone
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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TP53BP1 protein, human
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Trp53bp1 protein, mouse
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Tumor Suppressor p53-Binding Protein 1