Base excision repair is efficient in cells lacking poly(ADP-ribose) polymerase 1.
Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that is activated by binding to DNA breaks induced by ionizing radiation or through repair of altered bases in DNA by base excision repair. Mice lacking PARP-1 and, in certain cases, the cells derived from these mice exhibit hypersensitivity to ionizing radiation and alkylating agents. In this study we investigated base excision repair in cells lacking PARP-1 in order to elucidate whether their augmented sensitivity to DNA damaging agents is due to an impairment of the base excision repair pathway. Extracts prepared from wild-type cells or cells lacking PARP-1 were similar in their ability to repair plasmid DNA damaged by either X-rays (single-strand DNA breaks) or by N:-methyl-N:'-nitro-N:-nitrosoguanidine (methylated bases). In addition, we demonstrated in vivo that PARP-1-deficient cells treated with N:-methyl-N:'-nitro-N:-nitrosoguanidine repaired their genomic DNA as efficiently as wild-type cells. Therefore, we conclude that cells lacking PARP-1 have a normal capacity to repair single-strand DNA breaks inflicted by X-irradiation or breaks formed during the repair of modified bases. We propose that the hypersensitivity of PARP-1 null mutant cells to gamma-irradiation and alkylating agents is not directly due to a defect in DNA repair itself, but rather results from greatly reduced poly(ADP-ribose) formation during base excision repair in these cells.
Vodenicharov
M D
MD
Poly(ADP-ribose) Metabolism Group and DNA Repair Group, Health and Environment Unit, Laval University Medical Research Center, CHUQ and Faculty of Medicine, Laval University, 2705 Boulevard Laurier, Ste-Foy, Quebec G1V 4G2, Canada.
Sallmann
F R
FR
Satoh
M S
MS
Poirier
G G
GG
D000818:Animals; D020137:Base Pair Mismatch / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D002457:Cell Extracts; D002460:Cell Line; D002474:Cell-Free System; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D019175:DNA Methylation / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D004277:DNA, Single-Stranded / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts; D017353:Gene Deletion; D007700:Kinetics; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D051379:Mice; D008957:Models, Genetic; D009153:Mutagens / Q000494:pharmacology; D009243:NAD / Q000378:metabolism; D010957:Plasmids / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011836:Radiation Tolerance; D014965:X-Rays
D002457:Cell Extracts; D004277:DNA, Single-Stranded; D009153:Mutagens; D009243:NAD; D008769:Methylnitronitrosoguanidine; D011065:Poly(ADP-ribose) Polymerases