Poly(ADP-ribosyl)ation accelerates DNA repair in a pathway dependent on Cockayne syndrome B protein.
Activation of poly(ADP-ribose)polymerases 1 and 2 (PARP-1 and PARP-2) is one of the earliest responses of mammalian cells to DNA damage by numerous genotoxic agents. We have analysed the influence of PARP inhibition, either achieved by over-expression of the DNA binding domain of PARP-1 or by treatment with 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone, on the repair of single-strand breaks (SSB), pyrimidine dimers and oxidative base modifications sensitive to Fpg protein (mostly 8-hydroxyguanine) in mammalian cells at very low, non-cytotoxic levels of DNA damage. The data show that the repair rates of all three types of DNA damage are significantly lower in PARP-inhibited cells. Importantly, the retardation of the repair of base modifications is not associated with accumulation of intermediates such as SSB or abasic sites. Moreover, the influence of the PARP inhibition is not observed in cells deficient in Cockayne syndrome B protein (Csb). The results indicate that PARP activation and Csb are both involved in a novel mechanism that accelerates the global repair of various types of DNA modifications.
Flohr
Claudia
C
Institute of Pharmacy, University of Mainz, 55099 Mainz, Germany.
Bürkle
Alexander
A
Radicella
J Pablo
JP
Epe
Bernd
B
D000818:Animals; D002461:Cell Line, Transformed; D006224:Cricetinae; D004247:DNA / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D045643:DNA Repair Enzymes; D003907:Dexamethasone / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010880:Piperidines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D015398:Signal Transduction / Q000187:drug effects
D007546:Isoquinolines; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000075223:Poly-ADP-Ribose Binding Proteins; C108729:3,4-dihydro-5-(4-(1-piperidinyl)butoxy)-1(2H)-isoquinolinone; D003907:Dexamethasone; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases; D004265:DNA Helicases; C513075:Ercc6 protein, mouse; D045643:DNA Repair Enzymes