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- Title
Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.
- Authors
Bryant, Helen E; Schultz, Niklas; Thomas, Huw D; Parker, Kayan M; Flower, Dan; Lopez, Elena; Kyle, Suzanne; Meuth, Mark; Curtin, Nicola J; Helleday, Thomas
- Abstract
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.
- Publication
Nature, 2005, Vol 434, Issue 7035, p913
- ISSN
1476-4687
- Publication type
Journal Article
- DOI
10.1038/nature03443