Activation of the melanocortin 1 receptor (MC1R) by α-melanocortin (α-MSH) stimulates eumelanin synthesis and enhances repair of ultraviolet radiation (UV)-induced DNA damage. We report on the DNA damage response (DDR) of human melanocytes to UV and its enhancement by α-MSH. α-MSH up-regulated the levels of XPC, the enzyme that recognizes DNA damage sites, enhanced the UV-induced phosphorylation of the DNA damage sensors ataxia telangiectasia and Rad3-related (ATR) and ataxia telangiectasia mutated (ATM) and their respect-ive substrates checkpoint kinases 1 and 2, and increased phosphorylated H2AX (γH2AX) formation. These effects required functional MC1R and were absent in melanocytes expressing loss of function (LOF) MC1R. The levels of wild-type p53-induced phosphatase 1 (Wip1), which dephosphorylates γH2AX, correlated inversely with γH2AX. We propose that α-MSH increases UV-induced γH2AX to facilitate formation of DNA repair complexes and repair of DNA photoproducts, and LOF of MC1R compromises the DDR and genomic stability of melanocytes.
A 69-year-old woman presented for the evaluation of a slowly progressive, asymptomatic cutaneous eruption on her hands and forearms, as well as an enlarging, painful ulcer on her left leg that developed 6 months earlier. Her medical history was notable for essential thrombocytosis, which had been complicated by portal vein thrombosis, and she had been receiving treatment with hydroxyurea and rivaroxaban for the past 2 years. Despite worsening cutaneous disease, she otherwise felt well and denied associated fevers, weakness, weight loss, myalgias, arthralgias, or other constitutional symptoms.Physical examination revealed atrophic and reticulated violaceous plaques with a striking photoaccentuated distribution on the patient's dorsal hands and forearms (Figure , A). Scaly, violaceous plaques were also present on the thenar eminences and radial aspects of her first 2 fingers bilaterally (Figure , B). Prominent poikiloderma was seen on her sun-exposed chest and neck, and a large, stellate ulcer was present on her left distal lower leg (Figure , C). A lesional skin biopsy was performed on the patient's left forearm (Figure , D). Violaceous scaly plaques B Violaceous reticulated plaques A Shallow ulcer with stellate margins C Hematoxylin-eosin (original magnification ×100) D Figure. A, Clinical photograph of violaceous reticulated plaques on the dorsal aspect of the hands. B, Clinical photograph of violaceous, scaly plaques on the thenar and radial aspects of the thumb and second digit (mechanic hands). C, Clinical photograph of a shallow ulcer with stellate margins on the left distal lower leg. D, Histopathology (hematoxylin-eosin stain, original magnification x100). WHAT IS YOUR DIAGNOSIS? A. Cutaneous lupus erythematosus B. Cutaneous microvascular occlusion secondary to essential thrombocytosis C. Hydroxyurea-induced dermatomyositis-like eruption D. Polyarteritis nodosa Clinical Review & Education
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