The Eumelanin Human Skin Colour Scale: a proof-of-concept study.

BACKGROUND: At present there is no standard nomenclature for describing the diversity of human constitutive skin colour. OBJECTIVES: To develop a standard nomenclature to describe human constitutive skin colour. METHODS: Monthly focus group discussions were carried out among a multidisciplinary group of specialists over a 7-month period. Topics covered were (i) limitations and unmet needs of current nomenclature(s) pertaining to human cutaneous diversity, (ii) practical considerations about the function and role of any proposed nomenclature pertaining to human cutaneous diversity, (iii) review of the cellular basis and current molecular genetic understanding of variation in human skin pigmentation and (iv) in vivo methods to evaluate human skin pigmentation. In addition, a preliminary review of the published literature was undertaken to collate data on published skin reflectance measurements, notably melanin index values for well-referenced human populations. RESULTS: We developed a five-point scale to describe the full spectrum of human constitutive skin colour, termed the Eumelanin Human Skin Colour Scale. The nomenclature of the scale uses eumelanin, the dominant chromophore of human skin, as a central descriptive word. The categories of the scale (nomenclature and melanin index values) are eumelanin low (EML), < 25; eumelanin intermediate low (EMIL), 25 to < 50; eumelanin intermediate (EMI), 50 to < 75; eumelanin intermediate high (EMIH), 75 to < 100; and eumelanin high (EH), ≥ 100. CONCLUSIONS: The Eumelanin Human Skin Colour Scale enables the complete range of human constitutive skin colour to be described in an objective, equitable and understandable manner. In future, this scale can be used as the basis for developing other scales that address the specific functional aspects of human skin, such as response to ultraviolet radiation.

MSX1-Induced Neural Crest-Like Reprogramming Promotes Melanoma Progression.

Melanoma cells share many biological properties with neural crest stem cells. Here we show that the homeodomain transcription factor MSX1, which is significantly correlated with melanoma disease progression, reprograms melanocytes and melanoma cells toward a neural crest precursor-like state. MSX1-reprogrammed normal human melanocytes express the neural crest marker p75 and become multipotent. MSX1 induces a phenotypic switch in melanoma, which is characterized by an oncogenic transition from an E-cadherin-high nonmigratory state toward a ZEB1-high invasive state. ZEB1 up-regulation is responsible for the MSX1-induced migratory phenotype in melanoma cells. Depletion of MSX1 significantly inhibits melanoma metastasis in vivo. These results show that neural crest-like reprogramming achieved by a single factor is a critical process for melanoma progression.

A UVR-induced G2-phase checkpoint response to ssDNA gaps produced by replication fork bypass of unrepaired lesions is defective in melanoma.

UVR is a major environmental risk factor for the development of melanoma. Here we describe a coupled DNA-damage tolerance (DDT) mechanism and G2-phase cell cycle checkpoint induced in response to suberythemal doses of UVR that is commonly defective in melanomas. This coupled response is triggered by a small number of UVR-induced DNA lesions incurred during G1 phase that are not repaired by nucleotide excision repair (NER). These lesions are detected during S phase, but rather than stalling replication, they trigger the DDT-dependent formation of single-stranded DNA (ssDNA) gaps. The ssDNA attracts replication protein A (RPA), which initiates ATR-Chk1 (ataxia telangiectasia and Rad3-related/checkpoint kinase 1) G2-phase checkpoint signaling, and colocalizes with components of the RAD18 and RAD51 postreplication repair pathways. We demonstrate that depletion of RAD18 delays both the resolution of RPA foci and exit from the G2-phase arrest, indicating the involvement of RAD18-dependent postreplication repair in ssDNA gap repair during G2 phase. Moreover, the presence of RAD51 and BRCA1 suggests that an error-free mechanism may also contribute to repair. Loss of the UVR-induced G2-phase checkpoint results in increased UVR signature mutations after exposure to suberythemal UVR. We propose that defects in the UVR-induced G2-phase checkpoint and repair mechanism are likely to contribute to melanoma development.