Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair

• Published in: Nucleic acids research 2006-01, Vol.34 (6), p.1685-1691
• Main Authors: Bryant, Helen E., Helleday, Thomas
• Format: Article
• Language: English
• Subjects: 1-Naphthylamine - analogs & derivatives; 1-Naphthylamine - pharmacology; 1-Naphthylamine/analogs & derivatives/pharmacology; Animals; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins - metabolism; Cell Cycle Proteins - physiology; Cell Cycle Proteins/metabolism/physiology; Cell Line; Cell Survival; Cricetinae; DNA Repair; DNA-Activated Protein Kinase - metabolism; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; DNA-Binding Proteins/metabolism/physiology; Enzyme Activation; Enzyme Inhibitors - pharmacology; Gene Deletion; Mice; Mutation; Naphthalimides; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases/antagonists & inhibitors/genetics; Protein-Serine-Threonine Kinases - metabolism; Protein-Serine-Threonine Kinases - physiology; Protein-Serine-Threonine Kinases/metabolism/physiology; Quinolones - pharmacology; Recombination, Genetic; Tumor Suppressor Proteins - metabolism; Tumor Suppressor Proteins - physiology; Tumor Suppressor Proteins/metabolism/physiology
• ISSN: 0305-1048; 1362-4962; 1362-4962
• DOI: 10.1093/nar/gkl108

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).