Poly(ADP-ribose) polymerase (PARP) is an evolutionally conserved nuclear protein present in most eukaryotic species and catalyzes the formation of ADP-ribose polymers covalently attached to proteins. PARP is strongly activated by DNA single- or double-strand breaks and is thought to be involved in cellular responses to DNA damage. Based on the SV40-transformed Chinese hamster cell line CO60, we had established stable transfectants that overexpress the PARP DNA-binding domain conditionally. DNA-binding domain overexpression led to trans-dominant inhibition of poly(ADP-ribosyl)ation and sensitized the cells to genotoxic agents. Using the amplification of chromosomally integrated SV40 DNA as an indicator system, we show here that trans-dominant PARP inhibition potentiates genetic instability induced by N-methyl-N'-nitro-N-nitrosoguanidine treatment of cells.