Skin Cancer Induction by the Antimycotic Drug Voriconazole Is Caused by Impaired DNA Damage Detection Due to Chromatin Compaction.

Phototoxicity and skin cancer are severe adverse effects of the anti-fungal drug voriconazole (VOR). These adverse effects resemble those seen in xeroderma pigmentosum, caused by defective DNA nucleotide excision repair (NER), and we show that VOR decreases NER capacity. We show that VOR treatment does not perturb the expression of NER, or other DNA damage-related genes, but that VOR localizes to heterochromatin, in complexes containing histone acetyltransferase general control of amino-acid synthesis 5-like 2. Impairment of general control of amino-acid synthesis 5-like 2 binding to histone H3 reduced acetylation of H3, restricting damage-dependent chromatin unfolding, thereby reducing NER initiation. Restoration of H3 histone acetylation using histone deacetylase inhibitors, rescued VOR-induced NER repression, thus offering a preventive therapeutic option. These findings underline the importance of DNA damage-dependent chromatin remodeling as an important prerequisite of functional DNA repair.

Improved Spectral Purity of 222-nm Irradiation Eliminates Detectable Cyclobutylpyrimidine Dimers Formation in Skin Reconstructs even at High and Repetitive Disinfecting Doses.

UVC222 nm has germicidal effects with potential clinical applications. However, UVC irradiation is capable of inducing DNA damage like cyclobutylpyrimidine dimers (CPD). Although new devices have emission peaks in the short-wavelength region of UVC (~222 nm), the remaining "collateral" radiation at longer wavelengths could be harmful to human health. We investigated the DNA damage caused by far-UVC 222 nm KrCl exciplex radiation on human skin reconstructs after additional filtering using silica filters. The skin reconstructs were irradiated with 100 mJ cm-2 , 500 mJ cm-2 , and 3 × 500 mJ cm-2 unfiltered and filtered (230-270 nm suppressed) far-UVC or UVB (308 nm) radiation. UVB and non-filtered UVC irradiation induced a significant amount of CPDs, compared with the background. Filtered far-UVC lowered the CPD amount compared with unfiltered UVC and UVB treatments. Repetitive UVC irradiation did not result in the accumulation of CPDs compared with UVB treatment. Reduction in excess of 99.9% of E. coli, S. aureus and C. albicans was detected after applying far-UVC radiation. This identifies a therapeutic window in which microorganisms are killed but tissue is still alive and not damaged, which could give rise to new clinical applications.