RESUMEN
Phototoxicity and skin cancer are severe adverse effects of the anti-fungal drug Voriconazole (VOR). These adverse effects resemble those seen in xeroderma pigmentosum (XP), 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 GCN5. Impairment of GCN5 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 (HDACi), 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.
RESUMEN
Xeroderma pigmentosum (XP) is caused by defective nucleotide excision repair of DNA damage. This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads to premature death. The mechanism of neurodegeneration is unknown. Here, we investigate XP neurodegeneration using pluripotent stem cells derived from XP patients and healthy relatives, performing functional multi-omics on samples during neuronal differentiation. We show substantially increased levels of 5',8-cyclopurine and 8-oxopurine in XP neuronal DNA secondary to marked oxidative stress. Furthermore, we find that the endoplasmic reticulum stress response is upregulated and reversal of the mutant genotype is associated with phenotypic rescue. Critically, XP neurons exhibit inappropriate downregulation of the protein clearance ubiquitin-proteasome system (UPS). Chemical enhancement of UPS activity in XP neuronal models improves phenotypes, albeit inadequately. Although more work is required, this study presents insights with intervention potential.
Asunto(s)
Células Madre Pluripotentes Inducidas , Xerodermia Pigmentosa , Xerodermia Pigmentosa/patología , Xerodermia Pigmentosa/metabolismo , Xerodermia Pigmentosa/genética , Células Madre Pluripotentes Inducidas/metabolismo , Humanos , Neuronas/metabolismo , Neuronas/patología , Estrés Oxidativo , Estrés del Retículo Endoplásmico , Complejo de la Endopetidasa Proteasomal/metabolismo , Diferenciación Celular , Daño del ADN , Modelos Biológicos , MultiómicaRESUMEN
A síndrome de Cockayne (CS) é uma desordem autossômica recessiva caracterizada por nanismo, déficit de crescimento, deterioraçäo neurológica, fotossensibilidade e uma progressiva aparência facial característica. Neste artigo relatamos a primeira família brasileira com CS, cujo diagnóstico foi confirmado pela demonstraçäo de uma síntese diminuída de RNA na cultura de fibroblastos expostos à radiaçäo ultravioleta. Apesar do curso progressivo da doença e da inexistência de um tratamento efetivo, o diagnóstico faz-se muito importante, pois a família pode se beneficiar do aconselhamento genético e/ou do diagnóstico pré-natal.