Roles of poly(ADP-ribose) synthesis in repair and replication in normal human, Cockayne syndrome, and xeroderma pigmentosum fibroblasts after UV irradiation.
Roles of poly(ADP-ribose) in repair and replication were studied in UV-irradiated normal, xeroderma pigmentosum (XP), and Cockayne syndrome (CS) fibroblasts. UV radiation reduced cellular NAD with concurrent synthesis of poly-(ADP-ribose) in a dose-dependent manner in normal and CS cells, but not in XP cells. Enzymatic incision of DNA of UV-irradiated XP cells by T4-endonuclease V activated poly(ADP-ribose) polymerase. Methyl methanesulfonate (MMS) also reduced the cellular NAD in all the above strains. However, inhibitors of poly(ADP-ribose) synthesis did not affect UV-induced unscheduled DNA synthesis (UDS) and UV and MMS survivals. Thus, poly(ADP-ribose) synthesis may have a chromatin-stabilizing effect, but not the key role in excision repair of UV damage, unlike in the repair of dimethyl sulfate alkylation. CS cells were deficient in the NAD pool and in the recovery of post-UV DNA synthesis, which were rescued by an exogenous supply of NAD. Such normalization in CS cells was inhibited by excess nicotinamide as in normal cells, suggesting that replicon reinitiation may require specific poly(ADP-ribosyl)ation in UV-irradiated human cells.
D001549:Benzamides / Q000494:pharmacology; D003057:Cockayne Syndrome / Q000378:metabolism*; D004260:DNA Repair; D004261:DNA Replication; D004392:Dwarfism / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D066298:In Vitro Techniques; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D009243:NAD / Q000378:metabolism; D009702:Nucleoside Diphosphate Sugars / Q000096:biosynthesis*; D011064:Poly Adenosine Diphosphate Ribose / Q000096:biosynthesis*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000378:metabolism*
D001549:Benzamides; D009702:Nucleoside Diphosphate Sugars; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009243:NAD; D011064:Poly Adenosine Diphosphate Ribose; C025160:3-aminobenzamide; D008741:Methyl Methanesulfonate