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.
- MeSH
- buněčný cyklus MeSH
- chemorezistence genetika fyziologie MeSH
- chromozomální proteiny, nehistonové MeSH
- delece genu MeSH
- DNA vazebné proteiny MeSH
- embryonální kmenové buňky cytologie metabolismus MeSH
- geny BRCA1 * MeSH
- geny BRCA2 MeSH
- intracelulární signální peptidy a proteiny * antagonisté a inhibitory nedostatek genetika MeSH
- inzerční mutageneze MeSH
- lidé MeSH
- mutace * MeSH
- myši knockoutované MeSH
- myši MeSH
- nádorové buňky kultivované MeSH
- nádory prsu * farmakoterapie genetika metabolismus patologie MeSH
- oprava DNA MeSH
- poškození DNA MeSH
- proliferace buněk MeSH
- protein BRCA1 * nedostatek genetika MeSH
- protein BRCA2 nedostatek genetika MeSH
- proteiny regulující apoptózu MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
