Radiation-induced formation of purine 5',8-cyclonucleosides in isolated and cellular DNA: high stereospecificity and modulating effect of oxygen.
The present work is aimed at gaining conclusive mechanistic insights into the radiation-induced formation of the 5'R and 5'S diastereomers of both adenine and guanine 5',8-cyclo-2'-deoxyribonucleosides, with emphasis on the delineation of the inhibitory effect of O(2) in isolated and cellular DNA. The levels of purine 5',8-cyclo-2'-deoxyribonucleosides as assessed by HPLC-MS/MS were found to decrease steadily with the increase of O(2) concentration, the 5',8-cyclo-2'-deoxyguanosine being produced more efficiently than the 5',8-cyclo-2'-deoxyadenosine for low O(2) concentrations. A high stereoselectivity was observed in the intramolecular addition of the C5' radical to the C8 of the purine leading, after the creation of the C5'-C8 bond and a subsequent oxidation step, to the predominant formation of the 5'R diastereomer for both purine 5',8-cyclonucleosides. The reduced formation yield of the 4 tandem lesions in the presence of O(2) explains, at least partly, the low efficiency of radiation-induced yields of the purine 5',8-cyclo-2'-deoxyribonucleosides in cellular DNA, which are about two orders of magnitude lower than the previously reported data obtained from HPLC-MS analysis.
Belmadoui
Nourreddine
N
Laboratoire Lésions des Acides Nucléiques, DSM/INAC/SCIB UMR-E 3 CEA/UJF & FRE CNRS 3200CEA-Grenoble, 38054 Grenoble Cedex 9, France.
Boussicault
Fabien
F
Guerra
Maurizio
M
Ravanat
Jean-Luc
JL
Chatgilialoglu
Chryssostomos
C
Cadet
Jean
J
D000818:Animals; D002417:Cattle; D003500:Cyclization; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D005720:Gamma Rays; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D009000:Monocytes / Q000378:metabolism / Q000528:radiation effects; D010100:Oxygen / Q000494:pharmacology*; D011684:Purine Nucleosides / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D013379:Substrate Specificity; D014867:Water / Q000737:chemistry
D011684:Purine Nucleosides; D014867:Water; D017665:Hydroxyl Radical; D004247:DNA; D010100:Oxygen