Poly(ADP-ribose) polymerase inhibitors preserve oxidized nicotinamide adenine dinucleotide and adenosine 5'-triphosphate pools in DNA-damaged cells: mechanism of stimulation of unscheduled DNA synthesis

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Abstract
Inhibitors of poly(ADP-ribose) polymerase stimulated the level of DNA, RNA and protein synthesis in DNA-damaged [mouse leukemia] L1210 cells but had negligible effects in undamaged L1210 cells. The poly(ADP-ribose) polymerase inhibitors stimulated DNA repair synthesis after cells were exposed to high concentrations of N-methyl-N''-nitro-N-nitrosoguanidine (68 and 136 .mu.M) but not after exposure to low concentrations (13.6 and 34 .mu.M). When the L1210 cells were exposed to 136 .mu.M, N-methyl-N''-nitro-N-nitrosoguanidine, the activation of poly(ADP-ribose) polymerase resulted in the rapid depletion of NAD levels and subsequent depletion of ATP pools. After low doses of N-methyl-N''-nitrosoguanidine (13.6 .mu.M), there were only small decreases in NAD and ATP. Poly(ADP-ribose) polymerase inhibitors prevented the rapid fall in NAD and ATP pools. This preservation of the ATP pool has a permissive effect on energy-dependent functions and accounts for the apparent stimulation of DNA, RNA and protein synthesis. Thus, the mechanism by which poly(ADP-ribose) polymerase inhibitors stimulate DNA, RNA and protein synthesis in DNA-damaged cells appears to be mediated by their ability to prevent the drastic depletion of NAD pools that occurs in heavily damaged cells, thereby preserving the cells'' ability to generate ATP and maintain energy-dependent processes.