Several recent reports have demonstrated that photoreceptors are expressed in human skin. The rod and cone photoreceptor-like proteins are expressed in human skin and rhodopsin, long wavelength-opsin, and short wavelength-opsin are also present in cultured murine melanocytes. Furthermore, the photopigment rhodopsin is expressed in human melanocytes and is involved in ultraviolet A phototransduction which induces early melanin synthesis. In this study, we investigated whether rhodopsin is expressed and plays any physiological roles in the normal human epidermal keratinocytes (NHEKs). We found that rhodopsin was expressed and localized on the plasma membrane in NHEKs, and only violet light among several wavelengths within the visible range significantly increased the expression of rhodopsin mRNA. We further found that rhodopsin over-expression decreased the mRNA expression levels of keratinocyte differentiation markers, such as keratin-1 and keratin-10, and violet light also decreased the mRNA expression levels of keratinocyte differentiation markers and these decreased expression levels were recovered by a rhodopsin-directed siRNA. Moreover, we further demonstrated that violet light significantly decreased the phosphorylation levels of cAMP responsive element-binding protein (CREB) and that it more effectively decreased the phosphorylation of CREB when rhodopsin was over-expressed. In addition, we observed that pertussis toxin, a Gαi protein inhibitor, restored the rhodopsin-induced decrease in the differentiation markers in NHEKs. Taken together, these results suggest that rhodopsin down-regulates the expression levels of specific keratinocyte differentiation markers via the Gαi signaling pathway in NHEKs.

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RAP80 localizes to sites of DNA insults to enhance the DNA-damage responses. Here we identify TRAIP/RNF206 as a novel RAP80-interacting protein and find that TRAIP is necessary for translocation of RAP80 to DNA lesions. Depletion of TRAIP results in impaired accumulation of RAP80 and functional downstream partners, including BRCA1, at DNA lesions. Conversely, accumulation of TRAIP is normal in RAP80-depleted cells, implying that TRAIP acts upstream of RAP80 recruitment to DNA lesions. TRAIP localizes to sites of DNA damage and cells lacking TRAIP exhibit classical DNA-damage response-defect phenotypes. Biochemical analysis reveals that the N terminus of TRAIP is crucial for RAP80 interaction, while the C terminus of TRAIP is required for TRAIP localization to sites of DNA damage through a direct interaction with RNF20–RNF40. Taken together, our findings demonstrate that the novel RAP80-binding partner TRAIP regulates recruitment of the damage signalling machinery and promotes homologous recombination.

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Exposure to fine particulate matter (PM) with diameter <2.5 µm (PM2.5) causes epithelium injury and endothelial dysfunction. Primary cilia are sensory organelles that transmit extracellular signals into intracellular biochemical responses and have roles in physiology. To date, there have been no studies investigating whether PM2.5 affects primary cilia in skin. We addressed this in the present study using normal human epidermal keratinocytes (NHEKs) and retinal pigment epithelium (RPE) cells. We found that formation of primary cilium is increased in differentiated NHEKs. However, treatment with PM2.5 blocked increased ciliogenesis in NHEKs and RPE cells. Furthermore, PM2.5 transcriptionally upregulated small proline rich protein 3 (SPRR3) expression by activating c-Jun, and ectopic expression of SPRR3 inhibits suppressed the ciliogenesis. Accordingly, treatment with c-Jun activator (anisomycin) induced SPRR3 expression, whereas the inhibitor (SP600125) recovered the ciliated cells and cilium length in PM2.5-treated cells. Moreover, c-Jun inhibitor suppressed upregulation of SPRR3 in PM2.5-treated cells. Taken together, our finding suggested that PM2.5 inhibits ciliogenesis by increasing SPRR3 expression via c-Jun activation in RPE cells and keratinocytes.

Late epidermal differentiation is a key step of skin barrier formation; however, the specific genetic factors that distinguish late differentiation from early differentiation remain unknown. Here, we demonstrated that EGR3 is highly expressed in the stratum granulosum, and that it contributes to late epidermal differentiation. However, its expression is lost under poorly differentiated conditions, such as parakeratosis-lesional skin. EGR3 mediated the regulation of genes located in the epidermal differentiation complex through activation of enhancers and induction of enhancer RNAs. We further identified 20 targets of EGR3 specific for late differentiation. Additionally, we discovered that EGR3-and EGR3-related genes exhibited high tissue specificity on the skin. Through weighted gene co-expression analysis, EGR3 was found to be related to the keratinocyte differentiation-related module as an important part of the skin-specific genetic network. These findings shed light on the transcriptional regulation of late epidermal differentiation, highlighting candidate targets for diseases related to disrupted differentiation.

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The phototherapeutic effects of visible red light on skin have been extensively investigated, but the underlying biological mechanisms remain poorly understood. We aimed to elucidate the protective mechanism of visible red light in terms of DNA repair of UV-induced oxidative damage in normal human dermal fibroblasts. The protective effect of visible red light on UV-induced DNA damage was identified by several assays in both two-dimensional and three-dimensional cell culture systems. With regard to the protective mechanism of visible red light, our data showed alterations in base excision repair mediated by growth arrest and DNA damage inducible, alpha (GADD45A). We also observed an enhancement of the physical activity of GADD45A and apurinic/apyrimidinic endonuclease 1 (APE1) by visible red light. Moreover, UV-induced DNA damages were diminished by visible red light in an APE1-dependent manner. On the basis of the decrease in GADD45A-APE1 interaction in the activating transcription factor-2 (ATF2)-knockdown system, we suggest a role for ATF2 modulation in GADD45A-mediated DNA repair upon visible red light exposure. Thus, the enhancement of GADD45A-mediated base excision repair modulated by ATF2 might be a potential protective mechanism of visible red light.