Chemical excitation of electrons: A dark path to melanoma.
Sunlight's ultraviolet wavelengths induce cyclobutane pyrimidine dimers (CPDs), which then cause mutations that lead to melanoma or to cancers of skin keratinocytes. In pigmented melanocytes, we found that CPDs arise both instantaneously and for hours after UV exposure ends. Remarkably, the CPDs arising in the dark originate by a novel pathway that resembles bioluminescence but does not end in light: First, UV activates the enzymes nitric oxide synthase (NOS) and NADPH oxidase (NOX), which generate the radicals nitric oxide (NO) and superoxide (O2(-)); these combine to form the powerful oxidant peroxynitrite (ONOO(-)). A fragment of the skin pigment melanin is then oxidized, exciting an electron to an energy level so high that it is rarely seen in biology. This process of chemically exciting electrons, termed "chemiexcitation", is used by fireflies to generate light but it had never been seen in mammalian cells. In melanocytes, the energy transfers radiationlessly to DNA, inducing CPDs. Chemiexcitation is a new source of genome instability, and it calls attention to endogenous mechanisms of genome maintenance that prevent electronic excitation or dissipate the energy of excited states. Chemiexcitation may also trigger pathogenesis in internal tissues because the same chemistry should arise wherever superoxide and nitric oxide arise near cells that contain melanin.
Department of Therapeutic Radiology, Yale University School of Medicine, 333 Cedar St./HRT 213, New Haven, CT 06520-8040, USA. Electronic address: sanjay.premi@yale.edu.
Sanjay
S
Premi
Department of Therapeutic Radiology, Yale University School of Medicine, 333 Cedar St./HRT 213, New Haven, CT 06520-8040, USA; Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT 06520-8040 USA. Electronic address: douglas.brash@yale.edu.
Douglas E
DE
Brash
D004249:DNA Damage; D004583:Electrons; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D008543:Melanins / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism; D008545:Melanoma / Q000737:chemistry* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D009381:Neoplasms, Radiation-Induced / Q000737:chemistry* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000737:chemistry; D019001:Nitric Oxide Synthase / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000096:biosynthesis / Q000737:chemistry*; D011740:Pyrimidine Dimers / Q000096:biosynthesis / Q000737:chemistry; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D012878:Skin Neoplasms / Q000737:chemistry* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D013472:Sunlight / Q000009:adverse effects; D013481:Superoxides / Q000737:chemistry / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects
D008543:Melanins; D011740:Pyrimidine Dimers; D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases
Chemiexcitation; Cyclobutane pyrimidine dimer; Melanin; Melanoma; Nitric oxide; Peroxynitrite; Superoxide; Triplet state; Ultraviolet