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

By P. Bouwman, Amal Aly, J. Escandell, Mark Pieterse, J. Bártková, H. van der Gulden, S. Hiddingh, Maria Thanasoula, A. Kulkarni, Qifeng Yang and 10 more. Nature Structural &Molecular Biology, 2010

1,008 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/04c0e99616574540334f2c54252eaa30aa3fcf54

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In Molecular Biology

1. J. Bartek
2. J. Lukas
3. C. Lord
4. Alan Ashworth
5. C. Lukas
6. S. Boulton
7. Stephen P. Jackson
8. J. R. Chapman

In Oncology

1. J. Bartek
2. J. Lukas
3. C. Lukas
4. J. R. Chapman
5. C. Lord
6. S. Boulton
7. Alan Ashworth
8. Stephen J. Elledge

Citations in the corpus

• The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the misunderstandings (2011, background): “Furthermore, recent findings showing that loss of 53BP1 in BRCA1mutant cells alleviates hypersensitivity to PARP inhibitors and restores HR suggest a role for BRCA1 and 53BP1 in regulating the choice between HR and NHEJ pathways for DNA repair (Bouwman et al., 2010; Bunting et al., 2010).”
• Repair of strand breaks by homologous recombination. (2013, background): “Evidence indicates that 53bp1 disruption restores HR in BRCA1-deficient cells, likely by relieving 53BP1 inhibition of end resection at DSBs (Bouwman et al. 2010; Bunting et al. 2010).”
• A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. (2013, background): “Finally, it is important to evaluate the results presented herein in relation to BRCA1-deficient malignancies since the lethality, tumorigenesis, and PARP inhibitor sensitivity conferred by M BRCA1 deficiency can be suppressed by 53BP1 deletion (Bouwman et al., 2010; Bunting et al., 2010).”
• More than just a focus: The chromatin response to DNA damage and its role in genome integrity maintenance (2011, background): “Strikingly, several studies reported that genetic ablation of 53BP1 can restore homologous recombination in BRCA1-deficient cell”
• Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. (2012, neutral): “A model which would account for these observations is that the instability induced by loss of BRCA1 or BRCA2 could be transient and compensated during tumor progression by various mechanisms (47-49).”
• RIF1 Is Essential for 53BP1-Dependent Nonhomologous End Joining and Suppression of DNA Double-Strand Break Resection (2013, background): “A clear illustration of the antagonistic relationship between 53BP1 and BRCA1 is seen in mouse models, where the embryonic lethality, tumor predisposition, and HR defect of Brca1-deficient mice can be rescued by deleting 53BP1 (Bouwman et al., 2010; Bunting et al., 2010; Cao et al., 2009).”
• PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance (2020, background): “Depletion of 53BP1, a protein involved in the activation of NHEJ, rescues BRCA1-deficient HR and decreases hypersensitivity to PARP inhibitors (Bouwman et al., 2010).”
• The DNA Damage Response: Making it safe to play with knives (2010, background): “Indeed, BRCA2, BACH1, and PALB2 mutations predispose carriers to breast cancer formation when monoallelic and lead to FA syndrome—complementation groups D1, J, and N, respectively—when biallelic.”
• 53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress (2011, result): “Consistent with this hypothesis, recent studies showed that chromatin-associated DSB regulators suppress DNA end processin”
• Homologous recombination and human health: the roles of BRCA1, BRCA2 and associated proteins (2015, background): “Not surprisingly then, loss of 53BP1 does not rescue the viability of BRCA2-deficient cells, as it does with BRCA1-deficient cells (Bouwman et al. 2010).”