Mutations in sunlight-induced melanoma arise from cyclobutane pyrimidine dimers (CPD), DNA photoproducts that are typically created picoseconds after an ultraviolet (UV) photon is absorbed at thymine or cytosine. Here we show that in melanocytes, CPD are generated for >3 hours after exposure to UVA, a major component of the radiation in sunlight and in tanning beds. These “dark CPD” constitute the majority of CPD and include the cytosine-containing CPD that initiate UV-signature C→T mutations. Dark CPD arise when UV-induced reactive oxygen and nitrogen species combine to excite an electron in fragments of the pigment melanin. This creates a quantum triplet state that has the energy of a UV photon but that induces CPD by energy transfer to DNA in a radiation-independent manner. Melanin may thus be carcinogenic as well as protective against cancer. These findings also validate the long-standing suggestion that chemically-generated excited electronic states are relevant to mammalian biology.
Melanins can be classified into two major groups-insoluble brown to black pigments termed eumelanin and alkali-soluble yellow to reddish-brown pigments termed pheomelanin. Both types of pigment derive from the common precursor dopaquinone (ortho-quinone of 3,4-dihydroxyphenylalanine) which is formed via the oxidation of L-tyrosine by the melanogenic enzyme tyrosinase. Dopaquinone is a highly reactive ortho-quinone that plays pivotal roles in the chemical control of melanogenesis. In the absence of sulfhydryl compounds, dopaquinone undergoes intramolecular cyclization to form cyclodopa, which is then rapidly oxidized by a redox reaction with dopaquinone to give dopachrome (and dopa). Dopachrome then gradually and spontaneously rearranges to form 5,6-dihydroxyindole and to a lesser extent 5,6-dihydroxyindole-2-carboxylic acid, the ratio of which is determined by a distinct melanogenic enzyme termed dopachrome tautomerase (tyrosinase-related protein-2). Oxidation and subsequent polymerization of these dihydroxyindoles leads to the production of eumelanin. However, when cysteine is present, this process gives rise preferentially to the production of cysteinyldopa isomers. Cysteinyldopas are subsequently oxidized through redox reaction with dopaquinone to form cysteinyldopaquinones that eventually lead to the production of pheomelanin. Pulse radiolysis studies of early stages of melanogenesis (involving dopaquinone and cysteine) indicate that mixed melanogenesis proceeds in three distinct stages-the initial production of cysteinyldopas, followed by their oxidation to produce pheomelanin, followed finally by the production of eumelanin. Based on these data, a casing model of mixed melanogenesis is proposed in which a preformed pheomelanic core is covered by a eumelanic surface.
Subscribe to PCMR and stay up-to-date with the only journal committed to publishing basic research in melanoma and pigment cell biology As a member of the IFPCS or the SMR you automatically get online access to PCMR. Sign up as a member today at www.ifpcs.org or at www.societymelanomaresarch.org SummaryDespite considerable advances in the past decade, melanin research still suffers from the lack of universally accepted and shared nomenclature, methodologies, and structural models. This paper stems from the joint efforts of chemists, biochemists, physicists, biologists, and physicians with recognized and consolidated expertise in the field of melanins and melanogenesis, who critically reviewed and experimentally revisited methods, standards, and protocols to provide for the first time a consensus set of recommended procedures to be adopted and shared by researchers involved in pigment cell research. The aim of the paper was to define an unprecedented frame of reference built on cutting-edge knowledge and state-of-the-art methodology, to enable reliable comparison of results among laboratories and new progress in the field based on standardized methods and shared information.
Subscribe to PCMR and stay up-to-date with the only journal committed to publishing basic research in melanoma and pigment cell biology As a member of the IFPCS or the SMR you automatically get online access to PCMR. Sign up as a member today at www.ifpcs.org or at www.societymelanomaresarch.org
Eumelanin and pheomelanin in tissue samples can be specifically measured as the markers pyrrole-2,3,5-tricarboxylic acid (PTCA) and 4-amino-3-hydroxyphenylalanine after acidic permanganate oxidation and hydroiodic acid hydrolysis, respectively. Those degradation methods, although widely applied, are not easily performed in most laboratories. To overcome this difficulty, we developed alkaline H(2)O(2) oxidation in 1 M K(2)CO(3) that produces, in addition to the eumelanin marker PTCA, thiazole-2,4,5-tricarboxylic acid (TTCA) and thiazole-4,5-dicarboxylic acid (TDCA) as markers for pheomelanin and pyrrole-2,3-dicarboxylic acid (PDCA) as a marker for 5,6-dihydroxyindole-derived eumelanin. Those four degradation products can be easily separated by HPLC and analyzed with ultraviolet detection. The alkaline H(2)O(2) oxidation method is simple, reproducible and applicable to all pigmented tissues. Its application to characterize eumelanin and pheomelanin in human hair shows that PTCA and TTCA serve as specific markers for eumelanin and pheomelanin, respectively, although some caution is needed regarding the artificial production of TTCA from eumelanic tissue proteins.
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