Abstract
Unprotected exposure to UVB radiation from the sun and the resulting DNA damage are thought to be responsible for physiological changes in the skin and for a variety of skin cancers, including basal cell and squamous cell carcinoma and malignant melanoma. Although the mutagenic effects of UVB have been well documented and studied mechanistically, there is only limited information as to whether UV light may also be responsible for inducing epigenetic changes in the genome of exposed cells. DNA methylation is a stable epigenetic modification involved in gene control. To study the effects of UVB radiation on DNA methylation, we repeatedly exposed normal human keratinocytes to a UVB light source. After a recovery period, we analyzed global DNA methylation patterns in the irradiated and control cells using the methylated-CpG island recovery assay (MIRA) method in combination with high-resolution microarrays. Bioinformatics analysis revealed only a limited number of possible differences between UVB-exposed and control cells. However, these minor apparent changes could not be independently confirmed by bisulfite sequencing-based approaches. This study reveals that UVB irradiation of keratinocytes has no recognizable global effect on DNA methylation patterns and suggests that changes in DNA methylation, as observed in skin cancers, are not immediate consequences of human exposure to solar UVB irradiation.
Highlights
Solar UV light is divided into three wavelength categories: UVA with a wavelength between 320 nm and 400 nm, UVB with a wavelength between 280 nm and 320 nm, and far UV light (UVC) with a wavelength between 100 nm and 280 nm
Most of the skin cancer-causing effects of sunlight have been ascribed to UVB radiation with a smaller contribution from UVA1,2
One could conceive a scenario in which this exposure induces a signaling cascade and transcriptional changes inside cells that would affect DNA methylation patterns, for example by modulating the DNA methylation machinery or the chromatin state at genes that become susceptible to methylation. Such UV-induced heritable DNA methylation changes could lead to an altered phenotype and could provide a selective advantage to cells, perhaps when combined with UVB-induced mutations, and could be viewed as a tumor-driving event. We examined this hypothesis by exposing human keratinocytes chronically to UVB radiation and by assessing DNA methylation patterns on a genomic scale following UV exposure of cells and a recovery period
Summary
Solar UV light is divided into three wavelength categories: UVA with a wavelength between 320 nm and 400 nm, UVB with a wavelength between 280 nm and 320 nm, and far UV light (UVC) with a wavelength between 100 nm and 280 nm. UVB induces direct DNA damage through the formation of cyclobutane pyrimidine dimers (CPDs) and another dipyrimidine lesion, the (6-4) photoproduct[3,4,5,6] Of these two types of lesions, the CPD is thought to be responsible for the majority of mutations induced by UVB or sunlight irradiation[7,8]. 5-methylcytosines (mC), when part of a dipyrimidine sequence, are seen as preferential sites of CPD formation and as preferential mutational target sites in mammalian cells[9,10,11] These types of mutations, i.e. C or mC to T mutations at 5′TC, 5′CC, 5′TmC, and 5′CmC, are recognized as the major mutational events in human skin cancers, both in specific genes[4] and in large-scale genomic sequencing studies analyzing thousands of different genes simultaneously[12,13,14]
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