The DOI matches its Crossref record; 26 of the 26 references it cites were found in a registry or an index.
Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
Open accessAbstract
Poly(ADP-ribose) polymerase (PARP1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Nevertheless, PARP1-/- mice are viable, fertile and do not develop early onset tumours. Here, we show that PARP inhibitors trigger gamma-H2AX and RAD51 foci formation. We propose that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair. Furthermore, we show that BRCA2-deficient cells, as a result of their deficiency in homologous recombination, are acutely sensitive to PARP inhibitors, presumably because resultant collapsed replication forks are no longer repaired. Thus, PARP1 activity is essential in homologous recombination-deficient BRCA2 mutant cells. We exploit this requirement in order to kill BRCA2-deficient tumours by PARP inhibition alone. Treatment with PARP inhibitors is likely to be highly tumour specific, because only the tumours (which are BRCA2-/-) in BRCA2+/- patients are defective in homologous recombination. The use of an inhibitor of a DNA repair enzyme alone to selectively kill a tumour, in the absence of an exogenous DNA-damaging agent, represents a new concept in cancer treatment.
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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 [5]
In the citing paper
“Synthetic lethal interactions are of particular interest as they can be harnessed to identify new antibiotic or cancer therapeutic targets (6, 7).”
From A global genetic interaction network maps a wiring diagram of cellular function (2016) · cites this paper as [7]
Citations
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Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
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., et al. (2005) · Nature · doi:10.1038/nature03445 · Cited by 6,683
The DNA-damage response in human biology and disease
Jackson, S. P., & Bartek, J. (2009) · Nature · doi:10.1038/nature08467 · Cited by 6,092
Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers
Fong, P. C., Boss, D. S., Yap, T. A., Tutt, A., Wu, P., Mergui-Roelvink, M., Mortimer, P., Swaisland, H., Lau, A., O'Connor, M. J., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0900212 · Cited by 3,634
Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease
Bianchini, G., Balko, J. M., Mayer, I. A., Sanders, M. E., & Gianni, L. (2016) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.66 · Cited by 3,079
PARP inhibitors: Synthetic lethality in the clinic
Lord, C. J., & Ashworth, A. (2017) · Science · doi:10.1126/science.aam7344 · Cited by 3,013
Metadata
- Authors
- Bryant, H. E., Schultz, N., Thomas, H. D., Parker, K. M., Flower, D., Lopez, E., Kyle, S., Meuth, M., Curtin, N. J., & Helleday, T.
- Affiliations
- University of Sheffield (GB)
- Stockholm University (SE)
- Newcastle University (GB)
- Corresponding author
- Helleday, Thomas
- Venue
- Nature
- Published
- 2005-04-14
- Volume
- 434
- Issue
- 7035
- Pages
- 913-917
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2009007206
- Cited by
- 5,198
- References
- 26
- Citations by year
- 2026: 213 · 2025: 256 · 2024: 286 · 2023: 355 · 2022: 355 · 2021: 396 · 2020: 388 · 2019: 282 · 2018: 290 · 2017: 273 · 2016: 265 · 2015: 230 · 2014: 243 · 2013: 223 · 2012: 213
- FWCI
- 56.59
- Type
- journal article
- Language
- en
- Update notices
- erratum (2007-05-17)
- Open access
- green
- doi.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- 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
- PARP inhibitors, BRCA2 deficiency, homologous recombination, synthetic lethality, breast cancer, PARP1, DNA repair, replication fork collapse, single-strand breaks, γH2AX foci, RAD51 foci, base excision repair
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Animals, Antineoplastic Agents, Benzodiazepines, DNA Damage, DNA Repair, DNA Replication, Mice, Nude, Neoplasms, Poly(ADP-ribose) Polymerases, Xenograft Model Antitumor Assays, Genes, BRCA2, BRCA2 Protein, Cell Line, Tumor, Mice, Azulenes
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