Mono- and poly(ADP-ribose) metabolism following DNA damage.
Newly developed chemical methods have been applied to study ADP-ribosyl transferase reactions in intact cells following DNA damage. The intracellular levels of NAD and protein-bound monomeric and polymeric ADP-ribose residues were measured in cultured human cells following UV irradiation and in cultured mouse cells treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). UV irradiation of cells caused a rapid increase in the levels of poly(ADP-ribose). Individual molecules of the polymer are present only transiently and the overall rate of conversion of NAD to poly(ADP-ribose) is proportional to the cellular content of DNA strand breaks. Treatment of cells with MNNG also causes a rapid increase in the levels of both monomers and polymers of ADP-ribose. Non-toxic levels of members of two different classes of ADP-ribosyl transferase inhibitors prevent recovery of cell division following treatment of C3H10T1/2 cells with MNNG, while closely related compounds that are not inhibitory have no effect. These studies demonstrate that DNA damage results in a rapid perturbation of ADP-ribose metabolism and suggest that ADP-ribosyl transferase activity is necessary for cellular recovery from DNA damage.
D000246:Adenosine Diphosphate Ribose / Q000096:biosynthesis / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair; D005347:Fibroblasts / Q000528:radiation effects; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D009243:NAD / Q000378:metabolism; D009702:Nucleoside Diphosphate Sugars / Q000378:metabolism*; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases; D013806:Theophylline / Q000494:pharmacology; D014466:Ultraviolet Rays
D001549:Benzamides; D009702:Nucleoside Diphosphate Sugars; D009243:NAD; D008769:Methylnitronitrosoguanidine; D000246:Adenosine Diphosphate Ribose; D011064:Poly Adenosine Diphosphate Ribose; D004247:DNA; D013806:Theophylline; D011065:Poly(ADP-ribose) Polymerases; D009713:Nucleotidyltransferases; C025159:3-methoxybenzamide