UVA light induced mutagenesis in the exome of human nucleotide excision repair deficient cells

Skin cancer is associated with genetic mutations caused by exposure to sunlight radiation, mainly due to ultraviolet (UV) component that damages the DNA molecule. Although UVA has lower energy, it is the main solar UV component that reach the Earth's surface. However, UVA-induced mutagenesis and its role in the induction of skin cancer are still unclear. A strategy of whole exome sequencing of clones, from human XP-C cells (deficient on nucleotide excision repair, NER), was used to characterize somatic mutations induced by the UVA exposure. DNA sequence analysis of UVA-irradiated XP-C cells revealed a significative increment in the frequency of mutations in almost all types of base substitutions, but mostly at C>T transitions in the CCN and TCN trinucleotide context, which are potential sites for pyrimidine dimer formation. The C>T mutation mainly occurs at the 3' base of the 5'TC dimer and the CC>TT tandem mutations were also enriched. Additionally, it was possible to recover on the XP-C sequenced clones the SBS7 signature established in the COSMIC catalogue and related to skin cancer mutations. On the other hand, C>A transversions, traditionally related to oxidized guanines, was the second most frequently induced mutation. Therefore, this study provides evidence that pyrimidine dimers are the main type of lesion contributing to UVA induced mutagenesis on NER deficient human cells and that UVA generates mutational signatures similar to UVB irradiation.