Poly(ADP-ribose) polymerase (PARP-1) in homologous recombination and as a target for cancer therapy.
Poly(ADP-ribose) polymerase (PARP-1) binds to DNA breaks to facilitate DNA repair. However, the role of PARP-1 in DNA repair appears to not be critical since PARP-1 knockout mice are viable, fertile and do not develop early onset tumors. Cells isolated from these mice show an increased level of homologous recombination. There is an intricate link between homologous recombination and PARP-1 and a possible role for PARP-1 in DNA double-strand break repair. Although PARP-1 appears not to be required for homologous recombination itself, it regulates the process through its involvement in the repair of DNA single-strand breaks (SSBs). SSBs persisting into the S phase of the cell cycle collapse replication forks, triggering homologous recombination for replication restart. We discuss the recent discoveries on the use of PARP-1 inhibitors as a targeted cancer therapy for recombination deficient cancers, such as BRCA2 tumors.
Helleday
Thomas
T
The Institute for Cancer Studies, University of Sheffield, Medical School, Sheffield, UK. t.helleday@sheffield.ac.uk
Bryant
Helen E
HE
Schultz
Niklas
N
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle; D004249:DNA Damage; D004260:DNA Repair; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism / Q000502:physiology*; D011995:Recombination, Genetic; D016196:S Phase
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011065:Poly(ADP-ribose) Polymerases