Abstract LB-104: Excited electrons in melanin induce cyclobutane dimers in the dark

Abstract

Sunlight-induced melanomas contain UV-signature mutations, which are caused by cyclobutane pyrimidine dimers (CPD). These photoproducts are typically created picoseconds after a UV photon is absorbed at adjacent thymines or cytosines. However, using immunohistochemistry, mass spectrometry, and RNAi, we find that melanocytes generate CPD for >3 hours after exposure to UVA or UVB, wavelengths found in sunlight and in tanning beds; these “dark CPD” constitute the majority of CPD induced. Using pharmacologic inhibitors, single-photon counting, and specific energy acceptors, we elucidated the mechanism. The process begins when UV-induced superoxide and nitric oxide combine to form peroxynitrite, one of the few biological molecules capable of exciting an electron. Excitation creates a quantum triplet state in the skin pigment melanin that has the energy of a UV photon but induces CPD by transferring its energy to DNA in a radiation-independent manner. Melanin is evidently carcinogenic as well as protective. These findings may underlie the dependence of UV-induced and spontaneous skin cancers on melanin type. The results also validate the long-standing suggestion that chemical generation of excited electronic states - the source of bioluminescence in lower organisms - is important in mammalian biology. Citation Format: Sanjay Premi, Silvia Wallisch, Camila Mano, Adam Weiner, Antonella Bacchiocchi, Kazumasa Wakamatsu, Etelvino Bechara, Ruth Halaban, Thierry Douki, Douglas E. Brash. Excited electrons in melanin induce cyclobutane dimers in the dark. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-104. doi:10.1158/1538-7445.AM2015-LB-104

Radical-Enriched Artificial Melanin

“…17 Melanin consists of intrinsic indole semiquinone-like doublet-state radicals, which originate from an equilibrium between quinone and hydroquinone to yield semiquinone. 5,18,19 The radicals are the catalytic centers for superoxide decomposition 11 and can be utilized to determine the ratio between the two main types of mammalian melanin pigments: pheomelanin and eumelanin. 20 Developing radioprotective nanomaterials is of importance for myriad applications.…”

“…36 Its derivatives such as 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL) have been used for scavenging reactive oxygen species (ROS) as supplements for human health. 5,37,38 We hypothesized that, by introducing more stable radicals into synthetic melanin, we could enhance the X-ray protection properties of the resulting artificial melanin nanoparticles. This was tested by preparing radical-enriched melanin nanoparticles by copolymerization of a conventional dopamine monomer 1 with a radical-labeled monomer 2 (Figure 1).…”