53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers

P Bouwman, A Aly, JM Escandell, M Pieterse… - Nature structural & …, 2010 - nature.com
P Bouwman, A Aly, JM Escandell, M Pieterse, J Bartkova, H Van Der Gulden, S Hiddingh…
Nature structural & molecular biology, 2010nature.com
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 …
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.
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