Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy


BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination1, and mutations in these genes predispose to breast and other cancers2. Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks3. 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Depletion or inhibition of PARP1 selectively reduces the viability of BRCA1- and BRCA2-deficient ES cells.
Figure 2: DSB formation and repair after exposure to PARP inhibitor.
Figure 3: PARP inhibition selectively blocks the growth of BRCA2-deficient tumours in vivo.
Figure 4: A model for the selective effects of PARP inhibition on cells lacking wild-type BRCA1 and BRCA2.

Similar content being viewed by others


  1. Tutt, A. & Ashworth, A. The relationship between the roles of BRCA genes in DNA repair and cancer predisposition. Trends Mol. Med. 8, 571–576 (2002)

    Article  CAS  Google Scholar 

  2. Wooster, R. & Weber, B. Breast and ovarian cancer. N. Engl. J. Med. 348, 2339–2347 (2003)

    Article  CAS  Google Scholar 

  3. Hoeijmakers, J. H. Genome maintenance mechanisms for preventing cancer. Nature 411, 366–374 (2001)

    Article  ADS  CAS  Google Scholar 

  4. Schultz, N., Lopez, E., Saleh-Gohari, N. & Helleday, T. Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination. Nucleic Acids Res. 31, 4959–4964 (2003)

    Article  CAS  Google Scholar 

  5. Moynahan, M. E., Pierce, A. J. & Jasin, M. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol. Cell 7, 263–272 (2001)

    Article  CAS  Google Scholar 

  6. Moynahan, M. E., Chiu, J. W., Koller, B. H. & Jasin, M. Brca1 controls homology-directed DNA repair. Mol. Cell 4, 511–518 (1999)

    Article  CAS  Google Scholar 

  7. Tutt, A. et al. Mutation in Brca2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences. EMBO J. 20, 4704–4716 (2001)

    Article  CAS  Google Scholar 

  8. Foray, N. et al. A subset of ATM- and ATR-dependent phosphorylation events requires the BRCA1 protein. EMBO J. 22, 2860–2871 (2003)

    Article  CAS  Google Scholar 

  9. Kraakman-van der Zwet, M. et al. Brca2 (XRCC11) deficiency results in radioresistant DNA synthesis and a higher frequency of spontaneous deletions. Mol. Cell. Biol. 22, 669–679 (2002)

    Article  CAS  Google Scholar 

  10. Furuta, T. et al. Phosphorylation of histone H2AX and activation of Mre11, Rad50, and Nbs1 in response to replication-dependent DNA double-strand breaks induced by mammalian DNA topoisomerase I cleavage complexes. J. Biol. Chem. 278, 20303–20312 (2003)

    Article  CAS  Google Scholar 

  11. Bhattacharyya, A., Ear, U. S., Koller, B. H., Weichselbaum, R. R. & Bishop, D. K. The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. J. Biol. Chem. 275, 23899–23903 (2000)

    Article  CAS  Google Scholar 

  12. Dantzer, F., et al., Involvement of poly(ADP-ribose) polymerase in base excision repair. Biochimie 81, 69–75 (1999)

    Article  CAS  Google Scholar 

  13. Boulton, S., Kyle, S., & Durkacz, B. W. Interactive effects of inhibitors of poly(ADP-ribose) polymerase and DNA-dependent protein kinase on cellular to DNA damage. Carcinogenesis 20, 199–203 (1999)

    Article  CAS  Google Scholar 

  14. Haber, J. E. DNA recombination: the replication connection. Trends Biochem. Sci. 24, 271–275 (1999)

    Article  CAS  Google Scholar 

  15. Arnaudeau, C., Lundin, C. & Helleday, T. DNA double-strand breaks associated with replication forks are predominantly repaired by homologous recombination involving an exchange mechanism in mammalian cells. J. Mol. Biol. 307, 1235–1245 (2001)

    Article  CAS  Google Scholar 

  16. Lomonosov, M., Anand, S., Sangrithi, M., Davies, R. & Venkitaraman, A. R. Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein. Genes Dev. 17, 3017–3022 (2003)

    Article  CAS  Google Scholar 

  17. Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature doi:10.1038/nature03443 (this issue)

  18. Wang, Z. Q. et al. PARP is important for genomic stability but dispensable in apoptosis. Genes Dev. 11, 2347–2358 (1997)

    Article  CAS  Google Scholar 

  19. Turner, N., Tutt, A. & Ashworth, A. Hallmarks of BRCAness in sporadic cancers. Nature Rev. Cancer 4, 814–819 (2004)

    Article  CAS  Google Scholar 

  20. Loh, V. M. et al. Phthalazinones. Part 1: The design and synthesis of a novel series of potent inhibitors of poly(ADP-ribose) polymerase. Bioinorg. Med. Chem. Lett. (in the press)

  21. Ame, J.-C. et al. PARP-2, a novel mammalian DNA damage-dependent poly(ADP-ribose) polymerase. J. Biol. Chem. 274, 17860–17868 (1999)

    Article  CAS  Google Scholar 

  22. Kickhoefer, V. A. et al. The 193-kD vault protein, VPARP, is a novel poly(ADP-ribose) polymerase. J. Cell Biol. 146, 917–928 (1999)

    Article  CAS  Google Scholar 

  23. Dillon, K. J., Smith, G. C. M. & Martin, N. M. B. A flashplate assay for the identification of PARP-1 inhibitors. J. Biomol. Screen. 8, 347–352 (2003)

    Article  CAS  Google Scholar 

Download references


We thank Cancer Research UK, Breakthrough Breast Cancer and the Mary-Jean Mitchell Green Foundation for financial support. We thank I. Titley for help with FACS analysis, A. McCarthy and J. Williamson for help with chromosome spreads, E. Witt for western blot analysis, E. Iorns for real-time PCR analysis and M. Zdzienicka for V-C8 and V-C8 BAC cells. We also thank the Maybridge Chemical Company for their help in the design and synthesis of the PARP inhibitors.

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Graeme C. M. Smith or Alan Ashworth.

Ethics declarations

Competing interests

G.C.M.S., N.M.B.M., I.H., C.K. and K.J.D. are employees of KuDOS Pharmaceuticals Ltd. S.P.J. is the scientific founder and Chief Scientific Officer of KuDOS Pharmaceuticals Ltd. A patent application has been submitted by KuDOS and the Institute of Cancer Research based on these results.

Supplementary information

Supplementary Figures S1-S4

Supplementary Figure S1 describes the novel PARP inhibitor compounds used in this study. Supplementary Figure S2 shows a clonogenic experiment illustrating the rapid and irreversible effects of PARP inhibitors. Supplementary Figure S3 describes clonogenic experiments using Chinese Hamster Ovary and MCF7 cells and PARP inhibitors. Supplementary Figure S4 shows metaphase spreads, γH2AX assays and Rad51 assays. (PPT 1258 kb)

Supplementary Data

This file contains Supplementary Table S1, Supplementary Methods, Supplementary Figure Legends and additional references. (RTF 41 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Farmer, H., McCabe, N., Lord, C. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing