Poly(ADP-ribose) Polymerase inhibitors preserve nicotinamide adenine dinucleotide and adenosine 5'-triphosphate pools in DNA-damaged cells: mechanism of stimulation of unscheduled DNA synthesis.
Inhibitors of poly(ADP-ribose) polymerase stimulated the level of DNA, RNA, and protein synthesis in DNA-damaged 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 microM) but not after exposure to low concentrations (13.6 and 34 microM). When the L1210 cells were exposed to 136 microM N-methyl-N'-nitro-N-nitrosoguanidine, the activation of poly(ADP-ribose) polymerase resulted in the rapid depletion of oxidized nicotinamide adenine dinucleotide (NAD+) levels and subsequent depletion of adenosine 5'-triphosphate (ATP) pools. After low doses of N-methyl-N'-nitro-N-nitrosoguanidine (13.6 microM), 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.
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000096:biosynthesis; D007939:Leukemia L1210 / Q000201:enzymology; D008769:Methylnitronitrosoguanidine; D051379:Mice; D009243:NAD / Q000378:metabolism*; D009244:NAD+ Nucleosidase / Q000037:antagonists & inhibitors*; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009536:Niacinamide / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012334:RNA, Neoplasm / Q000096:biosynthesis
D001549:Benzamides; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012334:RNA, Neoplasm; D009243:NAD; D008769:Methylnitronitrosoguanidine; D009536:Niacinamide; C037689:benzamide; D000255:Adenosine Triphosphate; D004247:DNA; D009244:NAD+ Nucleosidase