53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA Breaks
Open accessAbstract
Defective DNA repair by homologous recombination (HR) is thought to be a major contributor to tumorigenesis in individuals carrying Brca1 mutations. Here, we show that DNA breaks in Brca1-deficient cells are aberrantly joined into complex chromosome rearrangements by a process dependent on the nonhomologous end-joining (NHEJ) factors 53BP1 and DNA ligase 4. Loss of 53BP1 alleviates hypersensitivity of Brca1 mutant cells to PARP inhibition and restores error-free repair by HR. Mechanistically, 53BP1 deletion promotes ATM-dependent processing of broken DNA ends to produce recombinogenic single-stranded DNA competent for HR. In contrast, Lig4 deficiency does not rescue the HR defect in Brca1 mutant cells but prevents the joining of chromatid breaks into chromosome rearrangements. Our results illustrate that HR and NHEJ compete to process DNA breaks that arise during DNA replication and that shifting the balance between these pathways can be exploited to selectively protect or kill cells harboring Brca1 mutations.
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Inactivation of 53BP1 restored homologous recombination to BRCA1-deficient cells.
“Remarkably, inactivation of one of these nonhomologous end-joining factors, 53BP1, restored homologous recombination to BRCA1-deficient cells [76,77].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [77]
BRCA1-deficient cells have homologous recombination defects due to an overactive nonhomologous end-joining pathway.
“In particular, BRCA1-deficient cells have defects in homologous recombination due to an overactive nonhomologous end-joining pathway.”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [77]
Loss of 53BP1 partly rescues the HR defect from BRCA1 deficiency, but not the defect in BARD1-deficient cells.
“Interestingly, even though depletion of 53BP1, an inhibitor of DNA end resection50, partially overcame the HR defect associated with BRCA1 deficiency (Extended Data Fig. 8h, i), it did not suppress the HR defect in BARD1 deficient cells (Extended Data Fig. 8j, k).”
From BRCA1–BARD1 promotes RAD51-mediated homologous DNA pairing (2017) · cites this paper as [50]
53BP1 and BRCA1 promote DSB signaling, and 53BP1 subsequently prevents DSB resection during HR.
“Although it seems counterintuitive for USP7 to both promote and limit 53BP1 and BRCA1 accumulation at sites of DSBs, an explanation may come from the finding that while 53BP1 and BRCA1 promote DSB signaling, 53BP1 subsequently prevent DSB resection during HR (Bunting et al., 2010; Coleman and Greenberg, 2011).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Bunting et al., 2010
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RETRACTED ARTICLE: A mechanism for the suppression of homologous recombination in G1 cells
Orthwein, A., Noordermeer, S. M., Wilson, M. D., Landry, S., Enchev, R. I., Sherker, A., Munro, M., Pinder, J., Salsman, J., Dellaire, G., et al. (2015) · Nature · doi:10.1038/nature16142 · Cited by 471 · see citing works
RetractedDNA Repair Pathway Choices in CRISPR-Cas9-Mediated Genome Editing
Xue, C., & Greene, E. C. (2021) · Trends in Genetics · doi:10.1016/j.tig.2021.02.008 · Cited by 431 · see citing works
BRCA1–BARD1 promotes RAD51-mediated homologous DNA pairing
Zhao, W., Steinfeld, J. B., Liang, F., Chen, X., Maranon, D. G., Jian Ma, C., Kwon, Y., Rao, T., Wang, W., Sheng, C., et al. (2017) · Nature · doi:10.1038/nature24060 · Cited by 393 · see citing works
SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling
Toiber, D., Erdel, F., Bouazoune, K., Silberman, D. M., Zhong, L., Mulligan, P., Sebastian, C., Cosentino, C., Martinez-Pastor, B., Giacosa, S., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.06.018 · Cited by 381 · see citing works
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Hereditary breast and ovarian cancer: new genes in confined pathways
Nielsen, F. C., van Overeem Hansen, T., & Sørensen, C. S. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.72 · Cited by 367 · see citing works
Therapeutic applications of PARP inhibitors: Anticancer therapy and beyond
Curtin, N. J., & Szabo, C. (2013) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2013.01.006 · Cited by 369 · see citing works
Thompson, L. H. (2012) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2012.06.002 · Cited by 357 · see citing works
DNA double-strand break repair pathway choice and cancer
Aparicio, T., Baer, R., & Gautier, J. (2014) · DNA Repair · doi:10.1016/j.dnarep.2014.03.014 · Cited by 347 · see citing works
Assembly and function of DNA double-strand break repair foci in mammalian cells
Bekker-Jensen, S., & Mailand, N. (2010) · DNA Repair · doi:10.1016/j.dnarep.2010.09.010 · Cited by 338 · see citing works
Xu, Y., Ayrapetov, M. K., Xu, C., Gursoy-Yuzugullu, O., Hu, Y., & Price, B. D. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.09.026 · Cited by 336 · see citing works
53BP1, BRCA1, and the Choice between Recombination and End Joining at DNA Double-Strand Breaks
Daley, J. M., & Sung, P. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.01639-13 · Cited by 318 · see citing works
Collaboration and competition between DNA double‐strand break repair pathways
Kass, E. M., & Jasin, M. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.07.057 · Cited by 326 · see citing works
BRCA1-associated exclusion of 53BP1 from DNA damage sites underlies temporal control of DNA repair
Chapman, J. R., Sossick, A. J., Boulton, S. J., & Jackson, S. P. (2012) · Journal of Cell Science · doi:10.1242/jcs.105353 · Cited by 327 · see citing works
RNF4, a SUMO-targeted ubiquitin E3 ligase, promotes DNA double-strand break repair
Galanty, Y., Belotserkovskaya, R., Coates, J., & Jackson, S. P. (2012) · Genes & Development · doi:10.1101/gad.188284.112 · Cited by 314 · see citing works
Goodarzi, A. A., Jeggo, P., & Lobrich, M. (2010) · DNA Repair · doi:10.1016/j.dnarep.2010.09.013 · Cited by 305 · see citing works
Nuclear Acetyl-CoA Production by ACLY Promotes Homologous Recombination
Sivanand, S., Rhoades, S., Jiang, Q., Lee, J. V., Benci, J., Zhang, J., Yuan, S., Viney, I., Zhao, S., Carrer, A., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.06.008 · Cited by 295 · see citing works
BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival
Gorrini, C., Baniasadi, P. S., Harris, I. S., Silvester, J., Inoue, S., Snow, B., Joshi, P. A., Wakeham, A., Molyneux, S. D., Martin, B., et al. (2013) · Journal of Experimental Medicine · doi:10.1084/jem.20121337 · Cited by 289 · see citing works
Targeting BRCA1 and BRCA2 Deficiencies with G-Quadruplex-Interacting Compounds
Zimmer, J., Tacconi, E. M. C., Folio, C., Badie, S., Porru, M., Klare, K., Tumiati, M., Markkanen, E., Halder, S., Ryan, A., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2015.12.004 · Cited by 261 · see citing works
“…Zimmer, Eliana M.C. Tacconi, Cecilia Folio, ..., Annamaria Biroccio, Julian E. Sale, Madalena Tarsounas Correspondence madalena.tarsounas@oncology.ox.ac.uk In Brief Zimmer et al. discovered that homologous recombination activities of BRCA1 and BRCA2…”
BackgroundInfluentialBRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair
Bunting, S. F., Callén, E., Kozak, M. L., Kim, J. M., Wong, N., López-Contreras, A. J., Ludwig, T., Baer, R., Faryabi, R. B., Malhowski, A., et al. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.02.015 · Cited by 252 · see citing works
Self-citationRegulation of DNA End Joining, Resection, and Immunoglobulin Class Switch Recombination by 53BP1
Bothmer, A., Robbiani, D. F., Di Virgilio, M., Bunting, S. F., Klein, I. A., Feldhahn, N., Barlow, J., Chen, H.-T., Bosque, D., Callen, E., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.03.019 · Cited by 244 · see citing works
Self-citationA Macrohistone Variant Links Dynamic Chromatin Compaction to BRCA1-Dependent Genome Maintenance
Khurana, S., Kruhlak, M. J., Kim, J., Tran, A. D., Liu, J., Nyswaner, K., Shi, L., Jailwala, P., Sung, M.-H., Hakim, O., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.07.024 · Cited by 220 · see citing works
Nuclear position dictates DNA repair pathway choice
Lemaître, C., Grabarz, A., Tsouroula, K., Andronov, L., Furst, A., Pankotai, T., Heyer, V., Rogier, M., Attwood, K. M., Kessler, P., et al. (2014) · Genes & Development · doi:10.1101/gad.248369.114 · Cited by 209 · see citing works
Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis.
Wang, Q., Ma, S., Song, N., Li, X., Liu, L., Yang, S., Ding, X., Shan, L., Zhou, X., Su, D., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci85747 · Cited by 206 · see citing works
HP1α recruitment to DNA damage by p150CAF-1 promotes homologous recombination repair
Baldeyron, C., Soria, G., Roche, D., Cook, A. J. L., & Almouzni, G. (2011) · Journal of Cell Biology · doi:10.1083/jcb.201101030 · Cited by 200 · see citing works
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Bouwman, P., van der Gulden, H., van der Heijden, I., Drost, R., Klijn, C. N., Prasetyanti, P., Pieterse, M., Wientjens, E., Seibler, J., Hogervorst, F. B. L., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0094 · Cited by 140 · see citing works
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BRCA1 and S phase DNA repair pathways restrict LINE-1 retrotransposition in human cells
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USP7 Is a Master Regulator of Genome Stability
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“Although it seems counterintuitive for USP7 to both promote and limit 53BP1 and BRCA1 accumulation at sites of DSBs, an explanation may come from the finding that while 53BP1 and BRCA1 promote DSB signaling, 53BP1 subsequently prevent DSB resection during HR (Bunting et al., 2010; Coleman and Greenberg, 2011).”
BackgroundMohni, K. N., Thompson, P. S., Luzwick, J. W., Glick, G. G., Pendleton, C. S., Lehmann, B. D., Pietenpol, J. A., & Cortez, D. (2015) · PLOS ONE · doi:10.1371/journal.pone.0125482 · Cited by 108 · see citing works
Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1
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“Remarkably, inactivation of one of these non homologous end-joining factors, 53BP1, restored homologous recombination to BRCA1-deficient cells [76,77].”
The role of BRCA1 in DNA double-strand repair: Past and present
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Interplays between ATM/Tel1 and ATR/Mec1 in sensing and signaling DNA double-strand breaks
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Lamin A/C-dependent interaction with 53BP1 promotes cellular responses to DNA damage
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USP7 deubiquitinase promotes ubiquitin-dependent DNA damage signaling by stabilizing RNF168.
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Hypoxia-induced miR-424 decreases tumor sensitivity to chemotherapy by inhibiting apoptosis
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The histone variant macroH2A1.1 is recruited to DSBs through a mechanism involving PARP1
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Induction of DNA double-strand breaks and cellular senescence by human respiratory syncytial virus
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Vitamin D/vitamin D receptor axis regulates DNA repair during oncogene-induced senescence
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p21 promotes error-free replication-coupled DNA double-strand break repair
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Cytoplasmic chromatin fragments-from mechanisms to therapeutic potential.
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Lamin B1 sequesters 53BP1 to control its recruitment to DNA damage
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An LTR retrotransposon‐derived lncRNA interacts with RNF169 to promote homologous recombination
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- Authors
- Bunting, S. F., Callén, E., Wong, N., Chen, H.-T., Polato, F., Gunn, A., Bothmer, A., Feldhahn, N., Fernandez-Capetillo, O., Cao, L., Xu, X., Deng, C.-X., Finkel, T., Nussenzweig, M., Stark, J. M., & Nussenzweig, A.
- Affiliations
- National Institutes of Health (US)
- Beckman Research Institute (US)
- Rockefeller University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Nussenzweig, André
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-04
- Volume
- 141
- Issue
- 2
- Pages
- 243-254
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2857570
- OpenAlex
- W2157899948
- Cited by
- 1,671
- References
- 67
- Citations by year
- 2026: 44 · 2025: 87 · 2024: 105 · 2023: 84 · 2022: 105 · 2021: 121 · 2020: 122 · 2019: 116 · 2018: 121 · 2017: 112 · 2016: 117 · 2015: 93 · 2014: 117 · 2013: 143 · 2012: 87
- FWCI
- 42.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Leukemia and Lymphoma Society
- National Institutes of Health (Z99 CA999999)
- National Cancer Institute (Z01BC010283, Z01BC010959, R01CA120954)
- National Institute of Allergy and Infectious Diseases (R37AI037526, R01AI037526, AI037526)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- 53BP1, BRCA1 deficiency, homologous recombination, non-homologous end joining, DNA resection, complex chromosomal rearrangements, PARP inhibition, ATM signaling, single-stranded DNA, BRCA1 mutation, carcinogenesis
- MeSH terms
- Tumor Suppressor p53-Binding Protein 1, Animals, B-Lymphocytes, Chromosomal Proteins, Non-Histone, DNA Repair, DNA-Binding Proteins, Female, Humans, BRCA1 Protein, Genomic Instability, Intracellular Signaling Peptides and Proteins, Mice, DNA Breaks
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