Repair and mutagenic potential of oxaluric acid, a major product of singlet oxygen-mediated oxidation of 8-oxo-7,8-dihydroguanine

Oxidative reactions within DNA commonly result in base modifications. Among the four DNA bases, guanine is the most susceptible to various oxidants, a nd its related oxidized form, 8-oxo-7,8-dihydroguanine, has been extensivel y studied in terms of repair and mutagenicity. However, 8-oxo-7,8-dihydrogu anine is readily subjected to further oxidation, and this has become a poin t of interest. We recently found that singlet oxygen oxidation of 8-oxo-7,8 -dihydroguanine fed to the predominant formation of oxaluric acid as the fi nal product. We report herein on the biological, features of oxaluric acid dealing with in vitro DNA synthesis and its removal from DNA by repair enzy mes. Nucleotide insertion opposite oxaluric acid, catalyzed by Kf exo(-) an d Taq indicates, that oxaluric acid induces G to T and G to C transversions . On the other hand, oxaluric acid represents a block when synthesis is per formed with pol beta. Interestingly, DNA repair experiments carried out wit h formamidopyrimidine DNA N-glycosylase (Fpg) and endonuclease III (endo II I) show that oxaluric acid is a substrate for both enzymes. Values of K-cat /K-m for the Fpg-mediated removal of oxidative guanine lesions revealed tha t 8-oxoGua is only a slightly better substrate than oxaluric acid. Interest ingly, the results obtained with endo III suggest that oxaluric acid is a m uch better substrate than is 5-hydroxycytosine (5-OHC), an oxidized pyrimid ine base.