Published online 23 March 2006
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Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair
1The Institute for Cancer Studies, University of Sheffield, Medical School Beech Hill Road, Sheffield S10 2RX, UK 2Department of Genetics Microbiology and Toxicology, Arrhenius Laboratory, Stockholm University S-106 91 Stockholm, Sweden
*To whom correspondence should be addressed. Tel: +44 114 271 29 93; Fax: +44 114 271 38 92; Email: t.helleday{at}sheffield.ac.uk
Received December 15, 2005. Revised January 12, 2006. Accepted March 8, 2006.
Poly (ADP-ribose) polymerase (PARP-1), ATM and DNA-dependent protein kinase (DNA-PK) are all involved in responding to DNA damage to activate pathways responsible for cellular survival. Here, we demonstrate that PARP-1–/– cells are sensitive to the ATM inhibitor KU55933 and conversely that AT cells are sensitive to the PARP inhibitor 4-amino-1,8-napthalamide. In addition, PARP-1–/– cells are shown to be sensitive to the DNA-PK inhibitor NU7026 and DNA-PKcs or Ku80 defective cells shown to be sensitive to PARP inhibitors. We believe PARP inhibition results in an increase in unresolved spontaneous DNA single-strand breaks (SSBs), which collapse replication forks and trigger homologous recombination repair (HRR). We show that ATM is activated following inhibition of PARP. Furthermore, PARP inhibitor-induced HRR is abolished in ATM, but not DNA-PK, inhibited cells. ATM and DNA-PK inhibition together give the same sensitivity to PARP inhibitors as ATM alone, indicating that ATM functions in the same pathways as DNA-PK for survival at collapsed forks, likely in non-homologous end joining (NHEJ). Altogether, we suggest that ATM is activated by PARP inhibitor-induced collapsed replication forks and may function upstream of HRR in the repair of certain types of double-strand breaks (DSBs).
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