The DOI matches its Crossref record; 24 of the 24 references it cites were found in a registry or an index.
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
Abstract
BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination, and mutations in these genes predispose to breast and other cancers. Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. We show here that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer.
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“Thus, BRCA-mutated cancer cells are selectively sensitive to agents that require repair of double-strand breaks by homologous recombination, such as PARP1 inhibitors [5–7].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [6]
Citations
Cites
Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
Bryant, H. E., Schultz, N., Thomas, H. D., Parker, K. M., Flower, D., Lopez, E., Kyle, S., Meuth, M., Curtin, N. J., & Helleday, T. (2005) · Nature · doi:10.1038/nature03443 · Cited by 5,198
Genome maintenance mechanisms for preventing cancer
Hoeijmakers, J. H. J. (2001) · Nature · doi:10.1038/35077232 · Cited by 3,939
Hallmarks of 'BRCAness' in sporadic cancers
Turner, N. C., Tutt, A. N. J., & Ashworth, A. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1457 · Cited by 1,690
Self-citationBrca1 Controls Homology-Directed DNA Repair
Moynahan, M. E., Chiu, J. W., Koller, B. H., & Jasin, M. (1999) · Molecular Cell · doi:10.1016/s1097-2765(00)80202-6 · Cited by 1,245
BRCA2 Is Required for Homology-Directed Repair of Chromosomal Breaks
Moynahan, M. E., Pierce, A. J., & Jasin, M. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00174-5 · Cited by 1,007
PARP-2, A Novel Mammalian DNA Damage-dependent Poly(ADP-ribose) Polymerase
Amé, J., Rolli, V., Schreiber, V., Niedergang, C., Apiou, F., Decker, P., Muller, S., Höger, T. H., Murcia, J. M., & de MURCIA, G. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.25.17860 · Cited by 744
Wooster, R., & Weber, B. (2003) · New England Journal of Medicine · doi:10.1056/nejmra012284 · Cited by 619
Bhattacharyya, A., Ear, U., Koller, B. H., Weichselbaum, R. R., & Bishop, D. K. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.c000276200 · Cited by 584
PARP is important for genomic stability but dispensable in apoptosisPreprint
Wang, Z., Stingl, L., Morrison, C. G., Jantsch, M. F., Łoś, M., Schulze‐Osthoff, K., & Wagner, E. F. (1997) · Genes & Development · doi:10.1101/gad.11.18.2347 · Cited by 557
Furuta, T., Takemura, H., Liao, Z.-Y., Aune, G. J., Redon, C., Sedelnikova, O. A., Pilch, D. R., Rogakou, E. P., Celeste, A., Chen, H. T., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300198200 · Cited by 449
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Metadata
- Authors
- Farmer, H., McCabe, N., Lord, C. J., Tutt, A. N. J., Johnson, D. A., Richardson, T. B., Santarosa, M., Dillon, K. J., Hickson, I., Knights, C., Martin, N. M. B., Jackson, S. P., Smith, G. C. M., & Ashworth, A.
- Affiliations
- Cancer Research UK (GB)
- Institute of Cancer Research (GB)
- Guy's Hospital (GB)
- University of Cambridge (GB)
- Corresponding author
- Smith, Graeme C. M.
- Ashworth, Alan
- ORCID
- Venue
- Nature
- Published
- 2005-04
- Volume
- 434
- Issue
- 7035
- Pages
- 917-921
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1973268287
- Cited by
- 6,683
- References
- 24
- Citations by year
- 2026: 271 · 2025: 346 · 2024: 356 · 2023: 454 · 2022: 443 · 2021: 502 · 2020: 460 · 2019: 382 · 2018: 381 · 2017: 353 · 2016: 358 · 2015: 315 · 2014: 312 · 2013: 292 · 2012: 262
- FWCI
- 68.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Cancer Research UK
- National Cancer Institute (F31CA260794)
- Topics
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- BRCA1, BRCA2, PARP inhibitors, homologous recombination, base excision repair, synthetic lethality, breast cancer, DNA double-strand break repair, chromosomal instability, cell cycle arrest, apoptosis, targeted cancer therapy
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Animals, Antineoplastic Agents, Cell Survival, DNA Damage, DNA Repair, Mice, Nude, Models, Biological, Mutation, Neoplasms, Poly(ADP-ribose) Polymerases, Substrate Specificity, Apoptosis, Genes, BRCA1, Xenograft Model Antitumor Assays, Genes, BRCA2, Mice
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