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Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase

An Addendum to this article was published on 17 May 2007

Abstract

Poly(ADP-ribose) polymerase (PARP1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage1,2,3. Nevertheless, PARP1-/- mice are viable, fertile and do not develop early onset tumours4. Here, we show that PARP inhibitors trigger γ-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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Figure 1: BRCA2-deficient cells are hypersensitive to inhibitors of PARP.
Figure 2: PARP1 and not PARP2 is important in preventing formation of a recombinogenic lesion, causing death in the absence of BRCA2.
Figure 3: BRCA2-deficient cells fail to repair a recombination lesion formed by inhibitors of PARP.
Figure 4: Specific killing of a BRCA2 tumour after a 5-day treatment with a PARP1 inhibitor in xenografts.

References

  1. Lindahl, T., Satoh, M. S., Poirier, G. G. & Klungland, A. Post-translational modification of poly(ADP-ribose) polymerase induced by DNA strand breaks. Trends Biochem. Sci. 20, 405–411 (1995)

    Article  CAS  Google Scholar 

  2. D'Amours, D., Desnoyers, S., D'Silva, I. & Poirier, G. G. Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem. J. 342, 249–268 (1999)

    Article  CAS  Google Scholar 

  3. El-Khamisy, S. F., Masutani, M., Suzuki, H. & Caldecott, K. W. A requirement for PARP-1 for the assembly or stability of XRCC1 nuclear foci at sites of oxidative DNA damage. Nucleic Acids Res. 31, 5526–5533 (2003)

    Article  CAS  Google Scholar 

  4. Conde, C. et al. Loss of poly(ADP-ribose) polymerase-1 causes increased tumour latency in p53-deficient mice. EMBO J. 20, 3535–3543 (2001)

    Article  CAS  Google Scholar 

  5. de Murcia, J. M. et al. Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc. Natl Acad. Sci. USA 94, 7303–7307 (1997)

    Article  ADS  CAS  Google Scholar 

  6. 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 

  7. Molinete, M. et al. Overproduction of the poly(ADP-ribose) polymerase DNA-binding domain blocks alkylation-induced DNA repair synthesis in mammalian cells. EMBO J. 12, 2109–2117 (1993)

    Article  CAS  Google Scholar 

  8. 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 

  9. Yang, Y. G., Cortes, U., Patnaik, S., Jasin, M. & Wang, Z. Q. Ablation of PARP-1 does not interfere with the repair of DNA double-strand breaks, but compromises the reactivation of stalled replication forks. Oncogene 23, 3872–3882 (2004)

    Article  CAS  Google Scholar 

  10. Griffin, C. S., Simpson, P. J., Wilson, C. R. & Thacker, J. Mammalian recombination-repair genes XRCC2 and XRCC3 promote correct chromosome segregation. Nature Cell Biol. 2, 757–761 (2000)

    Article  CAS  Google Scholar 

  11. Tebbs, R. S. et al. Correction of chromosomal instability and sensitivity to diverse mutagens by a cloned cDNA of the XRCC3 DNA repair gene. Proc. Natl Acad. Sci. USA 92, 6354–6358 (1995)

    Article  ADS  CAS  Google Scholar 

  12. Bowman, K. J., Newell, D. R., Calvert, A. H. & Curtin, N. J. Differential effects of the poly(ADP-ribose) polymerase (PARP) inhibitor NU1025 on topoisomerase I and II inhibitor cytotoxicity in L1210 cells in vitro . Br. J. Cancer 84, 106–112 (2001)

    Article  CAS  Google Scholar 

  13. Skalitzky, D. J. et al. Tricyclic benzimidazoles as potent poly(ADP-ribose) polymerase-1 inhibitors. J. Med. Chem. 46, 210–213 (2003)

    Article  CAS  Google Scholar 

  14. 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 

  15. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature doi:10.1038/nature03445 (this issue)

  16. Venkitaraman, A. R. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108, 171–182 (2002)

    Article  CAS  Google Scholar 

  17. Menissier de Murcia, J. et al. Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse. EMBO J. 22, 2255–2263 (2003)

    Article  CAS  Google Scholar 

  18. Lindahl, T. Instability and decay of the primary structure of DNA. Nature 362, 709–715 (1993)

    Article  ADS  CAS  Google Scholar 

  19. Paull, T. T. et al. A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr. Biol. 10, 886–895 (2000)

    Article  CAS  Google Scholar 

  20. 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 

  21. Caldecott, K. W., Tucker, J. D. & Thompson, L. H. Construction of human XRCC1 minigenes that fully correct the CHO DNA repair mutant EM9. Nucleic Acids Res. 20, 4575–4579 (1992)

    Article  CAS  Google Scholar 

  22. Calabrese, C. R. et al. Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. J. Natl Cancer Inst. 96, 56–67 (2004)

    Article  CAS  Google Scholar 

  23. Mohindra, A. et al. Defects in homologous recombination repair in mismatch-repair-deficient tumour cell lines. Hum. Mol. Genet. 11, 2189–2200 (2002)

    Article  CAS  Google Scholar 

  24. Halldorsson, H., Gray, D. A. & Shall, S. Poly (ADP-ribose) polymerase activity in nucleotide permeable cells. FEBS Lett. 85, 349–352 (1978)

    Article  CAS  Google Scholar 

  25. Grube, K., Kupper, J. H. & Burkle, A. Direct stimulation of poly(ADP ribose) polymerase in permeabilized cells by double-stranded DNA oligomers. Anal. Biochem. 193, 236–239 (1991)

    Article  CAS  Google Scholar 

  26. Lundin, C. et al. RAD51 is involved in repair of damage associated with DNA replication in mammalian cells. J. Mol. Biol. 328, 521–535 (2003)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We wish to thank J. Lunec, J. Thacker, L. Thompson, M. Zdzienicka, Z. Hostomsky and Pfizer GRD, La Jolla for providing materials. The investigation was financed by grants to T.H. and M.M from Yorkshire Cancer Research. Additional support was financed through grants to T.H. from the Swedish Cancer Society and the Swedish Research Council and a grant to N.J.C. from Cancer Research-UK.

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Correspondence to Thomas Helleday.

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Supplementary information

Supplementary Figure S1

HR deficient cells are hypersensitive to the toxic effect caused by inhibition of PARP-1. (DOC 72 kb)

Supplementary Figure S2

Description: PARP inhibition by NU1025 and AG14361 in BRCA2 deficient cells. (DOC 52 kb)

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Bryant, H., Schultz, N., Thomas, H. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005). https://doi.org/10.1038/nature03443

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