Mutagenic specificity of solar UV light in nucleotide excision repair-deficient rodent cells.

Abstract

To investigate the role of nucleotide excision repair (NER) in the cellular processing of carcinogenic DNA photoproducts induced by defined, environmentally relevant portions of the solar wavelength spectrum, we have determined the mutagenic specificity of simulated sunlight (310-1100 nm), UVA (350-400 nm), and UVB (290-320 nm), as well as of the "nonsolar" model mutagen 254-nm UVC, at the adenine phosphoribosyltransferase (aprt) locus in NERdeficient (ERCC1) Chinese hamster ovary (CHO) cells. The frequency distributions of mutational classes induced by UVB and by simulated sunlight in repair-deficient CHO cells were virtually identical, each showing a marked increase in tandem CC -> TT transitions relative to NER-proficient cells. A striking increase in CC --TT events was also previously documented for mutated p53 tumor-suppressor genes from nonmelanoma tumors of NER-deficient, skin cancer-prone xeroderma pigmentosum patients, compared to normal individuals. The data therefore indicate that the aprt gene in NER-deficient cultured rodent cells irradiated with artificial solar light generates the same distinctive "fingerprint" for sunlight mutagenesis as the p53 locus in NER-deficient humans exposed to natural sunlight in vivo. Moreover, in strong contrast to the situation for repair-competent CHO cells, where a significant role for UVA was previously noted, the mutagenic specificity of simulated sunlight in NER-deficient CHO cells and of natural sunlight in humans afflicted with xeroderma pigmentosum can be entirely accounted for by the UVB portion of the solar wavelength spectrum.

UVA radiation is highly mutagenic in cells that are unable to repair 7,8-dihydro-8-oxoguanine in Saccharomyces cerevisiae

“…Moreover, the currently available investigations on UVA mutagenesis generated very conflicting results, some reporting a majority of mutations at 8-oxoG (15) and others reporting a majority of mutations at CPDs (13,(16)(17)(18)43). One can argue that those discrepancies arose from different experimental conditions for UVA irradiation, damage detection, and mutagenesis.…”

“…Indeed, Besaratinia et al (15) observed a majority (25%) of GC3TA transversions in mouse embryonic fibroblasts, the expected mutation type for 8-oxoG. In contrast, this type of mutation is poorly represented in other studies (16)(17)(18), and the mutations found correlate with the formation of CPDs (13). In Chinese hamster ovary cells, the most prevalent UVA-induced mutational class was AT3CG transversion, whereas CG3TA transitions at dipyrimidine sites, the signature for CPDs, were also frequent (16).…”

Genome-wide comparison of human keratinocyte and squamous cell carcinoma responses to UVB irradiation: implications for skin and epithelial cancer

“…UVB irradiation rapidly induces two predominant types of specific DNA damage, namely pyrimidine dimers and [6-4] pyrimidine-pyrimidinone photoproducts (Pfeiffer, 1997). These lesions induce upregulation of DNA repair genes, mainly from the nucleotide excision repair (NER) machinery (Sage et al, 1996). In our list, several genes related to DNA repair are upregulated, including, the endonuclease ERCC1, the helicase ERCC2, and the pleiotropic genes GADD45A, GADD45B, TOB1, and BTG1 (category 3, Table 1).…”

A novel p53 mutational hotspot in skin tumors from UV-irradiated Xpc mutant mice alters transactivation functions

“…p53 mutational hotspots in skin tumors have revealed a distinctive fingerprint that is a hallmark of UV radiation-induced mutagenesis, namely tandem mutations at dipyrimidine sites (Sage et al, 1996). It has been proposed that mutation of one p53 allele in cells exposed to chronic UV radiation confers a phenotypic advantage due to a partial inhibition of the wild-type protein leading to less apoptosis of damaged 'sunburn' cells (Brash et al, 1996).…”