While the mutagenic and carcinogenic properties of longwave UV light (UVA) are well established, mechanisms of UVA mutagenesis remain a matter of debate. To elucidate the mechanisms of mutation formation with UVA in human skin, we determined the spectra of UVA- and UVB-induced mutations in primary human fibroblasts. As with UVB, we found the majority of mutations to be C-to-T transitions also with UVA. For both UVA and UVB, these transitions were found within runs of pyrimidines, at identical hotspots, and with the same predilection for the nontranscribed strand. They also included CC-to-TT tandem mutations. Therefore, these mutations point to a major role of pyrimidine dimers not only in UVB but also in UVA mutagenesis. While some differences were noted, the similarity between the spectra of UVA- and UVB-induced mutations further supports similar mechanisms of mutation formation. A non-dimer type of DNA damage does not appear to play a major role in either UVA or UVB mutagenesis. Therefore, the previously reported increasing mutagenicity per dimer with increasing wavelengths cannot be due to non-dimer DNA damage. Differences in the cellular response to UVA and UVB, such as the less prominent activation of p53 by UVA, might determine a different mutagenic outcome of UVA- and UVB-induced dimers.

Recombination repair plays an important role in the processing of DNA double-strand breaks (DSB) and DNA cross-links, and has been suggested to be mediated by the activation of the Fanconi anemia (FA)/BRCA pathway. Unlike DNA damage generated by ionizing radiation or DNA crosslinking, UV light-induced DNA damage is not commonly thought to require recombination for processing, as UV light does not directly induce DSBs or DNA cross-links. To elucidate the role of recombination repair in the cellular response to UV, we studied the FA/BRCA pathway in primary skin cells exposed to solar-simulated light. UV-induced monoubiquitination of the FANCD2 protein and formation of FANCD2 nuclear foci confirmed the activation of the pathway by UV light. This was only observed when cells were irradiated during S phase and was not caused by directly UV-induced DSBs. UV-exposed cells did not exhibit FANCD2 nuclear foci once they entered mitosis or when growth-arrested. In addition, UV-induced nuclear foci of the recombination proteins, RAD51 and BRCA1, colocalized with FANCD2 foci. We suggest that in response to UV light, when nucleotide excision repair failed to repair, or when translesional DNA synthesis failed to bypass UV-induced DNA photoproducts, the FA/BRCA pathway mediates the recombination repair of replication forks stalled at DNA photoproducts as a third line of defense. (Cancer Res 2006; 66(23): 11140-7)

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