Inhibition of poly(ADP-ribose)polymerase stimulates extrachromosomal homologous recombination in mouse Ltk- fibroblasts

Poly(ADP-ribose)polymerase (PARP) is an abundant nuclear enzyme activated b y DNA breaks. PARP is generally believed to play a role in maintaining the integrity of the genome in eukaryote cells via antire-combinogenic activity by preventing inappropriate homologous recombination reactions at DNA doub le-strand breaks. While inhibition of PARR reduces non-homologous recombina tion, at the same time it stimulates sister chromatid exchange and intrachr omosomal homologous recombination. Here we report that the inhibition of PA RP with 100 mu g/ml (0.622 mM) 1,5-isoquinolinediol results in an average 4 .6-fold increase in the frequency of extrachromosomal homologous recombinat ion between two linearized plasmids carrying herpes simplex virus thymidine kinase genes inactivated by non-overlapping mutations, in mouse Ltk- fibro blasts. These results are in disagreement with the previously reported obse rvation that PARP inhibition had no effect on extrachromosomal homologous r ecombination in Ltk- cells.