Abstract
Variants in the melanocortin-1 receptor (MC1R) gene, encoding a trimeric G-protein-coupled receptor and activated by α-melanocyte-stimulating hormone (α-MSH), are frequently associated with red or blonde hair, fair skin, freckling, and skin sensitivity to ultraviolet (UV) light. Several red hair color variants of MC1R are also associated with increased melanoma risk. MC1R variants affect melanoma risk independent of phenotype. Here, we demonstrated that MC1R is a critical factor in chromosome stability and centromere integrity in melanocytes. α-MSH/MC1R stimulation prevents melanocytes from UV radiation-induced damage of chromosome stability and centromere integrity. Mechanistic studies indicated that α-MSH/MC1R-controlled chromosome stability and centromeric integrity are mediated by microphthalmia-associated transcription factor (Mitf), a transcript factor needed for the α-MSH/MC1R signaling and a regulator in melanocyte development, viability, and pigment production. Mitf directly interacts with centromere proteins A in melanocytes. Given the connection among MC1R variants, red hair/fair skin phenotype, and melanoma development, these studies will help answer a question with clinical relevance “why red-haired individuals are so prone to developing melanoma”, and will lead to the identification of novel preventive and therapeutic strategies for melanomas, especially those with redheads.
Highlights
Skin color is determined by epidermal melanin, the function of which remains poorly understood
It remains unclear whether the level of melanocortin-1 receptor (MC1R) impacts genome stability, which is sensitively responded to UV radiation (UVR) in melanocytes
Human primary melanocytes with either wild-type MC1R or MC1R silencing were stimulated with α-melanocyte-stimulating hormone (α-MSH) (10 μM) before irradiation with 100 J/m2 UVB, a dosage that generates standard erythema in UVB
Summary
Skin color is determined by epidermal melanin, the function of which remains poorly understood. There is a lower incidence of melanoma in individuals with high levels of constitutive brown/black pigment and/or acquired pigmentation (e.g., tanning). Individuals with red hair, blue eyes, and inability to tan are at higher risk for developing melanoma. In Caucasians, melanoma risk is up to tripled in red/red-blonde-. The melanocortin-1 receptor (MC1R) plays a crucial role in tanning and pigmentation in humans and mice. MC1R is a trimeric G-protein-coupled receptor that is activated by the α-melanocyte-stimulating hormone (αMSH)[1]. Upon α-MSH binding, MC1R activates the cAMP signaling pathway and promotes melanin production in melanocytes. Α-MSH/MC1R signaling functions in DNA repair after ultraviolet (UV) irradiation[2,3,4] Upon α-MSH binding, MC1R activates the cAMP signaling pathway and promotes melanin production in melanocytes. α-MSH/MC1R signaling functions in DNA repair after ultraviolet (UV) irradiation[2,3,4]
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