UVA (320 -400 nm) radiation constitutes >90% of the environmentally relevant solar UV radiation, and it has been proposed to have a role in skin cancer and aging. Because of the popularity of UVA tanning beds and prolonged periods of sunbathing, the potential deleterious effect of UVA has emerged as a source of concern for public health. Although generally accepted, the impact of DNA damage on the cytotoxic, mutagenic, and carcinogenic effect of UVA radiation remains unclear. In the present study, we investigated the sensitivity of a panel of yeast mutants affected in the processing of DNA damage to the lethal and mutagenic effect of UVA radiation. The data show that none of the major DNA repair pathways, such as base excision repair, nucleotide excision repair, homologous recombination, and postreplication repair, efficiently protect yeast from the lethal action of UVA radiation. In contrast, the results show that the Ogg1 DNA glycosylase efficiently prevents UVA-induced mutagenesis, suggesting the formation of oxidized guanine residues. Furthermore, sequence analysis of UVA-induced canavanine-resistant mutations reveals a bias in favor of GC3 TA events when compared with spontaneous or H2O2-, UVC-, and ␥-ray-induced canavanine-resistant mutations in the WT strain. Taken together, our data point out a major role of oxidative DNA damage, mostly 7,8-dihydro-8-oxoguanine, in the genotoxicity of UVA radiation in the yeast Saccharomyces cerevisiae. Therefore, the capacity of skin cells to repair 7,8-dihydro-8-oxoguanine may be a key parameter in the mutagenic and carcinogenic effect of UVA radiation in humans.base excision repair ͉ OGG1 ͉ mutagenesis ͉ DNA photolesions U VA radiation has been proposed to have a role in skin cancer and aging (1). UVA (320-400 nm) constitutes Ͼ90% of the environmentally relevant solar UV radiation. Because of the popularity of the high-intensity UVA tanning equipment and the widespread use of efficient UVB-absorbing sunscreens blocking erythema and often accompanied by prolonged periods of sunbathing, the human exposure to UVA have increased significantly in the last decades. The deleterious effect of UVA has, as a consequence, recently emerged as a source of concern for public health (2, 3).Although very complex, the biological effect of UVA radiation is at least partially related to DNA damage. Despite it being well established that UVA can damage DNA, to date, the nature of the lesions underlying its mutagenic and carcinogenic effects remains controversial. Unlike UVB photons, which are directly absorbed by DNA and cause the formation of cis-syn cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts, the UVA component of solar radiation is poorly absorbed by DNA. Rather, UVA radiation excites other endogenous chromophores, generating reactive oxygen species, some of which are possibly involved in the outcome of photocarcinogenesis (4, 5). It is generally accepted that UVA damages DNA, either through the generation of singlet oxygen ( 1 O 2 ) or by a type...

7,8-dihydro-8-oxoguanine (8-oxoG) is an abundant and mutagenic lesion produced in DNA exposed to free radicals and reactive oxygen species. In Saccharomyces cerevisiae, the OGG1 gene encodes the 8-oxoG DNA N-glycosylase/AP lyase (Ogg1), which is the functional homologue of the bacterial Fpg. Ogg1-deficient strains are spontaneous mutators that accumulate GC to TA transversions due to unrepaired 8-oxoG in DNA. In yeast, DNA mismatch repair (MMR) and translesion synthesis (TLS) by DNA polymerase eta also play a role in the prevention of the mutagenic effect of 8-oxoG. In the present study, we show the RAD18 and RAD6 genes that are required to initiate post-replication repair (PRR) are also involved in the prevention of mutations by 8-oxoG. Consistently, a synergistic increase in spontaneous CanR and Lys+ mutation rates is observed in the absence of Rad6 or Rad18 proteins in ogg1 mutant strains. Spectra of CaR mutations in ogg1 rad18 and ogg1 rad6 double mutants show a strong bias in the favor of GC to TA transversions, which are 137- and 189-fold higher than in the wild-type, respectively. The results also show that Poleta (RAD30 gene product) plays a critical role on the prevention of mutations at 8-oxoG, whereas Polzeta (REV3 gene product) does not. Our current model suggests that the Rad6-Rad18 complex targets Poleta at DNA gaps that result from the MMR-mediated excision of adenine mispaired with 8-oxoG, allowing error-free dCMP incorporation opposite to this lesion.