Involvement of poly(ADP-ribose) polymerase in base excision repair

Poly(ADP-ribose) polymerase (PARP) is a zinc-finger DNA binding protein tha t detects and signals DNA strand breaks generated directly or indirectly by genotoxic agents. In response to these lesions, the immediate poly(ADP-rib osylation) of nuclear proteins converts DNA interruptions into intracellula r signals that activate DNA repair or cell death programs. To elucidate the biological function of PARP in vivo, the mouse PARP gene was inactivated b y homologous recombination to generate mice lacking a functional PARP gene. PARP knockout mice and the derived mouse embryonic fibroblasts (MEFs) were acutely sensitive to monofunctional alkylating agents and gamma-irradiatio n demonstrating that PARP is involved in recovery from DNA damage that trig gers the base excision repair (BER) process. To address the issue of the ro le of PARP in BER, the ability of PARP-deficient mammalian cell extracts to repair a single abasic site present on a circular duplex plasmid molecule was tested in a standard in vitro repair assay. The results clearly demonst rate, for the first time, the involvement of PARP in the DNA synthesis step of the base excision repair process. (C) Societe francaise de biochimie et biologie moleculaire / Elsevier, Paris.