Skin Cancer Induction by the Antimycotic Drug Voriconazole Is Caused by Impaired DNA Damage Detection Due to
Sara Giovannini1, Lisa Weibel2, Birgit Schittek3
1Department of Dermatology, University Regensburg, Regensburg, Germany; Department of Dermatology, Eberhard Karls University, Tuebingen, Germany.
Abstract:
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.
Insights
The antifungal drug voriconazole (VOR) impairs DNA repair, leading to skin toxicity. Restoring histone acetylation can prevent this, offering a new therapeutic strategy for managing VOR side effects.
Area of Science:
- Molecular Biology
- Genetics
- Dermatology
Background:
- Voriconazole (VOR), an antifungal, causes phototoxicity and skin cancer.
- These effects mimic xeroderma pigmentosum, linked to defective DNA nucleotide excision repair (NER).
Purpose of the Study:
- To investigate the mechanism by which VOR impairs NER capacity.
- To explore therapeutic strategies to counteract VOR-induced DNA damage response inhibition.
Main Methods:
- Assessing NER capacity in VOR-treated cells.
- Analyzing gene expression of NER and DNA damage-related genes.
- Investigating VOR localization and its interaction with chromatin modifiers.
- Evaluating the impact of histone acetylation modulation on NER.
Main Results:
- VOR treatment reduces NER capacity without altering gene expression.
- VOR localizes to heterochromatin, interacting with histone acetyltransferase general control of amino-acid synthesis 5-like 2 (GCN5L2).
- Impaired GCN5L2 binding to histone H3 reduces H3 acetylation, hindering chromatin unfolding and NER initiation.
- Histone deacetylase inhibitors restore H3 acetylation and rescue VOR-induced NER repression.
Conclusions:
- VOR-induced phototoxicity and skin cancer are mediated by impaired NER due to chromatin remodeling defects.
- Targeting histone acetylation offers a potential preventive therapy for VOR-related adverse effects.
- DNA damage-dependent chromatin remodeling is crucial for functional DNA repair.
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