Alterations in deoxynucleoside triphosphate metabolism in DNA damaged cells: identification and consequences of poly(ADP-ribose) polymerase dependent and independent processes.
Treatment of L1210 cells with increasing concentrations of MNNG produces heterogeneous perturbations of cellular deoxynucleoside triphosphate pools, with the magnitude and direction of the shift depending on the deoxynucleotide and on the concentration and time of exposure of the DNA damaging agent. 5 microM MNNG stimulated an increase in dATP, dCTP and dTTP but dGTP pools remained constant. These increases were not affected by 3-aminobenzamide, indicating that the pool size increases were produced by poly(ADP-ribose) polymerase independent reactions. 30 microM MNNG caused a time dependent decrease in dATP, dGTP, dTTP and dCTP. The dGTP pool was most drastically affected, becoming totally depleted within 3 hours. The fall in all 4 dNTP pools was substantially prevented by 3-aminobenzamide, suggesting that the decrease in dNTPs following DNA damage is mediated by a poly(ADP-ribose) polymerase dependent reaction. Severe depression of dGTP pools consequent to NAD and ATP depletion may provide a metabolic pathway for rapidly stopping DNA synthesis as a consequence of DNA damage and the activation of poly(ADP-ribose) polymerase.
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair; D003854:Deoxyribonucleotides / Q000378:metabolism*; D004789:Enzyme Activation; D007939:Leukemia L1210; D008769:Methylnitronitrosoguanidine / Q000633:toxicity*; D051379:Mice; D009243:NAD / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*
D001549:Benzamides; D003854:Deoxyribonucleotides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009243:NAD; D008769:Methylnitronitrosoguanidine; C025160:3-aminobenzamide; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases