1. The Institute for Cancer Studies, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK
2. Department of Genetics, Microbiology and Toxicology, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden
3. Northern Institute for Cancer Research, University of Newcastle upon Tyne, Medical School, Newcastle upon Tyne, NE2 4HH, UK

Correspondence to: Thomas Helleday^1,2 Correspondence and requests for materials should be addressed to T.H. (Email: t.helleday@sheffield.ac.uk).

Abstract

Poly(ADP-ribose) polymerase (PARP1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage^{1, 2, 3}. Nevertheless, PARP1^-/- mice are viable, fertile and do not develop early onset tumours⁴. Here, we show that PARP inhibitors trigger -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.

1. The Institute for Cancer Studies, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK
2. Department of Genetics, Microbiology and Toxicology, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden
3. Northern Institute for Cancer Research, University of Newcastle upon Tyne, Medical School, Newcastle upon Tyne, NE2 4HH, UK

Correspondence to: Thomas Helleday^1,2 Correspondence and requests for materials should be addressed to T.H. (Email: t.helleday@sheffield.ac.uk).

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