10779/crick.12631277.v1 Reto Brem Reto Brem Peter Macpherson Peter Macpherson Melisa Guven Melisa Guven Peter Karran Peter Karran Oxidative stress induced by UVA photoactivation of the tryptophan UVB photoproduct 6-formylindolo[3,2-b]carbazole (FICZ) inhibits nucleotide excision repair in human cells The Francis Crick Institute 2020 Carbazoles DNA Damage DNA Repair Humans Oxidation-Reduction Oxidative Stress Tryptophan Ultraviolet Rays Karran FC001098 0601 Biochemistry and Cell Biology 0299 Other Physical Sciences 2020-07-15 11:02:34 Journal contribution https://crick.figshare.com/articles/journal_contribution/Oxidative_stress_induced_by_UVA_photoactivation_of_the_tryptophan_UVB_photoproduct_6-formylindolo_3_2-b_carbazole_FICZ_inhibits_nucleotide_excision_repair_in_human_cells/12631277 Potentially mutagenic DNA lesions induced by UVB (wavelengths 280-320 nm) are important risk factors for solar ultraviolet (UV) radiation-induced skin cancer. The carcinogenicity of the more abundant UVA (320-400 nm) is less well understood but is generally regarded to reflect its interaction with cellular chromophores that act as photosensitisers. The arylhydrocarbon receptor agonist 6-formylindolo[3,2-b] carbazole (FICZ), is a UVB photoproduct of tryptophan and a powerful UVA chromophore. Combined with UVA, FICZ generates reactive oxygen species (ROS) and induces oxidative DNA damage. Here we demonstrate that ROS generated by FICZ/UVA combinations also cause extensive protein damage in HaCaT human keratinocytes. We show that FICZ/UVA-induced oxidation significantly inhibits the removal of potentially mutagenic UVB-induced DNA photolesions by nucleotide excision repair (NER). DNA repair inhibition is due to FICZ/UVA-induced oxidation damage to the NER proteome and DNA excision repair is impaired in extracts prepared from FICZ/UVA-treated cells. NER protects against skin cancer. As a likely UVB photoproduct of intracellular tryptophan, FICZ represents a de facto endogenous UVA photosensitiser in sun-exposed skin. FICZ formation may increase the risk of solar UV-induced skin cancer by promoting photochemical damage to the NER proteome and thereby preventing the removal of UVB-induced DNA lesions.