The REV‐ERB antagonist SR8278 modulates keratinocyte viability in response to UVA and UVB radiation

Mar 9, 2024Photochemistry and photobiology

REV-ERB blocker SR8278 changes skin cell survival after UVA and UVB exposure

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Abstract

SR8278 may promote keratinocyte viability in UVB-irradiated cells but has limited utility for UV photoprotection.

SR8278 did not significantly affect the nucleotide excision repair process or the expression of the clock-regulated NER factor XPA.
Both KS15 and SR8278 absorb UV light, which may limit initial UV photoproduct formation in DNA.
SR8278 increased cell viability in UVB-irradiated keratinocytes, even when the core circadian clock protein BMAL1 was disrupted.
SR8278 sensitized keratinocytes to UVA light, potentially due to toxic reactive oxygen species production.
Results suggest SR8278 could lead to phototoxicity in humans or mammals exposed to solar radiation.

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The nucleotide excision repair (NER) system removes UV photoproducts from genomic DNA and is controlled by the circadian clock. Given that small-molecule compounds have been developed to target various clock proteins, we examined whether the cryptochrome inhibitor KS15 and REV-ERB antagonist SR8278 could modulate keratinocyte responses to UV radiation in vitro. We observed that though SR8278 promoted cell viability in UVB-irradiated cells, it had little effect on NER or on the expression of the clock-regulated NER factor XPA. Rather, we found that both KS15 and SR8278 absorb light within the UV spectrum to limit initial UV photoproduct formation in DNA. Moreover, SR8278 promoted UVB viability even in cells in which the core circadian clock protein BMAL1 was disrupted, which indicates that SR8278 is likely acting via other REV-ERB transcriptional targets. We further observed that SR8278 sensitized keratinocytes to light sources containing primarily UVA wavelengths of light likely due to the generation of toxic reactive oxygen species. Though other studies have demonstrated beneficial effects of SR8278 in other model systems, our results here suggest that SR8278 has limited utility for UV photoprotection in the skin and will likely cause phototoxicity in humans or mammals exposed to solar radiation.

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The REV‐ERB antagonist SR8278 modulates keratinocyte viability in response to UVA and UVB radiation

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