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Cell-intrinsic melanin fails to protect melanocytes from ultraviolet-mutagenesis in the absence of epidermal melanin.

ABSTRACT: Melanin is a free-radical scavenger, antioxidant, and broadband absorber of ultraviolet (UV) radiation which protects the skin from environmental carcinogenesis. However, melanin synthesis and UV-induced reactive melanin species are also implicated in melanocyte genotoxicity. Here, we attempted to reconcile these disparate functions of melanin using a UVB-sensitive, NRAS-mutant mouse model, TpN. We crossed TpN mice heterozygous for an inactivating mutation in Tyrosinase to produce albino and black littermates on a C57BL/6J background. These animals were then exposed to a single UVB dose on postnatal day three when keratinocytes in the skin have yet to be melanized. Approximately one-third (35%) of black mice were protected from UVB-accelerated tumor formation. However, melanoma growth rates, tumor mutational burdens, and gene expression profiles were similar in melanomas from black and albino mice. Skin from albino mice contained more cyclobutane pyrimidine dimer (CPD) positive cells than black mice 1-h post-irradiation. However, this trend gradually reversed over time with CPDs becoming more prominent in black than albino melanocytes at 48 h. These results show that in the absence of epidermal pigmentation, melanocytic melanin limits the tumorigenic effects of acute UV exposure but fails to protect melanocytes from UVB-induced mutagenesis.

SUBMITTER: Weiss TJ

PROVIDER: S-EPMC10092168 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Cell-intrinsic melanin fails to protect melanocytes from ultraviolet-mutagenesis in the absence of epidermal melanin.

Weiss Tirzah J TJ Crawford Emma R ER Posada Valentina V Rahman Hafeez H Liu Tong T Murphy Brandon M BM Arnold Tiffany E TE Gray Shannon S Hu Zhexuan Z Hennessey Rebecca C RC Yu Lianbo L D'Orazio John A JA Burd Craig J CJ Zippin Jonathan H JH Grossman Douglas D Burd Christin E CE

Pigment cell & melanoma research 20221009 1

Melanin is a free-radical scavenger, antioxidant, and broadband absorber of ultraviolet (UV) radiation which protects the skin from environmental carcinogenesis. However, melanin synthesis and UV-induced reactive melanin species are also implicated in melanocyte genotoxicity. Here, we attempted to reconcile these disparate functions of melanin using a UVB-sensitive, NRAS-mutant mouse model, TpN. We crossed TpN mice heterozygous for an inactivating mutation in Tyrosinase to produce albino and bla ...[more]

PMID: 36148789

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Project description:BackgroundHuman skin, which is constantly exposed to solar ultraviolet radiation (UVR), has a unique ability to respond by increasing its pigmentation in a protective process driven by melanogenesis in human epidermal melanocytes (HEMs). However, the molecular mechanisms used by HEMs to detect and respond to UVR remain unclear.ObjectivesTo investigate the function and potential mechanism of opsin 5 (OPN5), a photoreceptor responsive to UVR wavelengths, in melanogenesis in HEMs.MethodsMelanin content in HEMs was determined using the NaOH method, and activity of tyrosinase (TYR) (a key enzyme in melanin synthesis) was determined by the l-DOPA method. OPN5 expression in UVR-treated vs. untreated HEMs and explant tissues was detected by reverse-transcription quantitative polymerase chain reaction (RT-qPCR), Western blotting and immunofluorescence. Short interfering RNA-mediated OPN5 knockdown and a lentivirus OPN5 overexpression model were used to examine their respective effects on TYR, tyrosinase-related protein 1 (TRP1), TRP2 and microphthalmia-associated transcription factor (MITF) expression, under UVR. Changes in expression of TYR, TRP1 and TRP2 caused by changes in OPN5 expression level were detected by RT-qPCR and Western blot. Furthermore, changes in signalling pathway proteins were assayed.ResultsWe found that OPN5 is the key sensor in HEMs responsible for UVR-induced melanogenesis. OPN5-induced melanogenesis required Ca2+ -dependent G protein-coupled receptor- and protein kinase C signal transduction, thus contributing to the UVR-induced MITF response to mediate downstream cellular effects, and providing evidence of OPN5 function in mammalian phototransduction. Remarkably, OPN5 activation was necessary for UVR-induced increase in cellular melanin and has an inherent function in melanocyte melanogenesis.ConclusionsOur results provide insight into the molecular mechanisms of UVR sensing and phototransduction in melanocytes, and may reveal molecular targets for preventing pigmentation or pigment diseases.

Dataset Information

Cell-intrinsic melanin fails to protect melanocytes from ultraviolet-mutagenesis in the absence of epidermal melanin.

Publications

Cell-intrinsic melanin fails to protect melanocytes from ultraviolet-mutagenesis in the absence of epidermal melanin.

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