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Trivalent arsenicals enhance UVA-associated genomic instability in human keratinocyte models

ABSTRACT: Inorganic arsenic is a well-established human carcinogen strongly associated with non-melanoma skin cancer, yet its interaction with solar radiation remains incompletely understood. Arsenic-related tumors arise preferentially in sun-exposed regions and frequently exhibit mutational patterns associated with oxidative stress rather than classical ultraviolet B signatures, implicating ultraviolet A (UVA) radiation as a potential co-exposure factor. Here, we evaluated the effects of physiologically relevant concentrations of trivalent arsenicals on UVA-associated genomic instability using keratinocyte models differing in p53 status. A multi-endpoint platform integrating comet assay kinetics, micronucleus analysis, Bliss synergy modeling, and transcriptomic profiling was used to characterize combinational responses. Sub-micromolar arsenicals alone produced minimal cytotoxicity and negligible increases in comet-detectable DNA damage. In contrast, co-exposure with UVA significantly increased chromosomal instability, particularly in p53-deficient and p53-mutant cells, despite limited additional comet signal. Repair kinetics demonstrated efficient lesion resolution in primary keratinocytes, whereas monomethylarsonous acid (MMA(III)) selectively impaired repair progression in p53-mutant HaCaT cells. Transcriptomic analysis identified altered expression of replication- and checkpoint-associated pathways in transformed keratinocytes. Across models, micronucleus formation was disproportionately elevated relative to measurable strand-break induction, indicating a dissociation between initial DNA damage and downstream genomic outcomes. Collectively, these findings support a model in which arsenicals enhance UVA-associated genomic instability by altering the processing and persistence of oxidative DNA damage rather than substantially increasing initial lesion burden.

ORGANISM(S): Homo sapiens

PROVIDER: GSE336622 | GEO | 2026/06/30

REPOSITORIES: GEO

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Trivalent arsenicals enhance UVA-associated genomic instability in human keratinocyte models

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