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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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
Cites
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
Instability and decay of the primary structure of DNA
Lindahl, T. (1993) · Nature · doi:10.1038/362709a0 · Cited by 5,679
A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage
Paull, T. T., Rogakou, E. P., Yamazaki, V., Kirchgessner, C. U., Gellert, M., & Bonner, W. M. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00610-2 · Cited by 2,098
Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions
D’Amours, D., Desnoyers, S., D’Silva, I., & Poirier, G. G. (1999) · Biochemical Journal · doi:10.1042/bj3420249 · Cited by 1,819
Cancer Susceptibility and the Functions of BRCA1 and BRCA2
Venkitaraman, A. R. (2002) · Cell · doi:10.1016/s0092-8674(02)00615-3 · Cited by 1,713
Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells
Murcia, J. M., Niedergang, C., Trucco, C., Ricoul, M., Dutrillaux, B., Mark, M. P., Oliver, F. J., Masson, M., Dierich, A., LeMeur, M., et al. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.14.7303 · Cited by 1,058
El‐Khamisy, S. F. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg761 · Cited by 689
Murcia, J. M., Ricoul, M., Tartier, L., Niedergang, C., Huber, A., Dantzer, F., Schreiber, V., Amé, J., Dierich, A., LeMeur, M., et al. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg206 · Cited by 629
Post-translational modification of poly(ADP-ribose) polymerase induced by DNA strand breaks
Lindahl, T. L., Satoh, M. S., Poirier, G. G., & Klungland, A. (1995) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(00)89089-1 · Cited by 611
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
Cited by
Sorted by citations
Items 1,001–1,021 of 1,021
Pharmacogenetics in Breast Cancer Therapy
Tan, S., Lee, S. C., Goh, B.-C., & Wong, J. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-0993 · Cited by 86
How to kill tumor cells with inhibitors of poly(ADP‐ribosyl)ation
Mangerich, A., & Bürkle, A. (2010) · International Journal of Cancer · doi:10.1002/ijc.25683 · Cited by 85
Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response
Mandal, J., Mandal, P., Wang, T.-L., & Shih, I.-M. (2022) · Journal of Biomedical Science · doi:10.1186/s12929-022-00856-5 · Cited by 84
Radiation induced DNA DSBs: Contribution from stalled replication forks?
Harper, J. V., Anderson, J. A., & O’Neill, P. (2010) · DNA Repair · doi:10.1016/j.dnarep.2010.06.002 · Cited by 78
Lucas, A. L., Frado, L. E., Hwang, C., Kumar, S., Khanna, L. G., Levinson, E. J., Chabot, J. A., Chung, W. K., & Frucht, H. (2014) · Cancer · doi:10.1002/cncr.28662 · Cited by 68
Hypoxia-inducible factor in cancer: from pathway regulation to therapeutic opportunity
Ortmann, B. M. (2024) · BMJ Oncology · doi:10.1136/bmjonc-2023-000154 · Cited by 67
A Comparative Genomic Approach for Identifying Synthetic Lethal Interactions in Human Cancer
Deshpande, R., Asiedu, M. K., Klebig, M., Sutor, S., Kuzmin, E., Nelson, J., Piotrowski, J., Ho Shin, S., Yoshida, M., Costanzo, M., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-3956 · Cited by 64
DNA repair mechanisms protect our genome from carcinogenesis
Moraes, M. C. S. (2012) · Frontiers in Bioscience · doi:10.2741/3992 · Cited by 64
Hereditary breast cancer: From molecular pathology to tailored therapies
Tan, D. S. P., Marchiò, C., & Reis-Filho, J. S. (2008) · Journal of Clinical Pathology · doi:10.1136/jcp.2008.057950 · Cited by 60
Dickey, J. S., Gonzalez, Y., Aryal, B., Mog, S., Nakamura, A. J., Redon, C. E., Baxa, U., Rosen, E., Cheng, G., Zielonka, J., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0070575 · Cited by 60
The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer
Abraham, J. E., Pinilla, K., Dayimu, A., Grybowicz, L., Demiris, N., Harvey, C., Drewett, L. M., Lucey, R., Fulton, A., Roberts, A. N., et al. (2024) · Nature · doi:10.1038/s41586-024-07384-2 · Cited by 53
Understanding Resistance Mechanisms and Expanding the Therapeutic Utility of PARP Inhibitors
Lim, J., & Tan, D. S. P. (2017) · Cancers · doi:10.3390/cancers9080109 · Cited by 52
BRCA1- and BRCA2-related mutations: therapeutic implications in ovarian cancer
Pothuri, B. (2013) · Annals of Oncology · doi:10.1093/annonc/mdt307 · Cited by 50
Pancreas cancer and BRCA : A critical subset of patients with improving therapeutic outcomes
Momtaz, P., O’Connor, C. A., Chou, J. F., Capanu, M., Park, W., Bandlamudi, C., Berger, M. F., Kelsen, D. P., Suehnholz, S. P., Chakravarty, D., et al. (2021) · Cancer · doi:10.1002/cncr.33812 · Cited by 44
Yang, C.-S., Jividen, K., Kamata, T., Dworak, N., Oostdyk, L., Remlein, B., Pourfarjam, Y., Kim, I.-K., Du, K.-P., Abbas, T., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23055-6 · Cited by 44
Targeting DNA Damage Response and Immune Checkpoint for Anticancer Therapy
Huang, J.-L., Chang, Y.-T., Hong, Z.-Y., & Lin, C.-S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063238 · Cited by 42
Leveraging microenvironmental synthetic lethalities to treat cancer
Metcalf, K. J., Alazzeh, A., Werb, Z., & Weaver, V. M. (2021) · Journal of Clinical Investigation · doi:10.1172/jci143765 · Cited by 42
Prediction of Genetic Interactions Using Machine Learning and Network Properties
Madhukar, N. S., Elemento, O., & Pandey, G. (2015) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2015.00172 · Cited by 39
The combination of olaparib and camptothecin for effective radiosensitization
Miura, K., Sakata, K.-I., Someya, M., Matsumoto, Y., Matsumoto, H., Takahashi, A., & Hareyama, M. (2012) · Radiation Oncology · doi:10.1186/1748-717x-7-62 · Cited by 33
Sun, L., Liu, Y., Guo, X., Cui, T., Wu, C., Tao, J., Cheng, C., Chu, Q., Ji, C., Li, X., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-49573-7 · Cited by 18
Federico, M. B., Siri, S. O., Calzetta, N. L., Paviolo, N. S., de la Vega, M. B., Martino, J., Campana, M. C., Wiesmüller, L., & Gottifredi, V. (2020) · Oncogene · doi:10.1038/s41388-020-1265-9 · Cited by 12
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
