Most cyclobutane-pyrimidine dimers (CPD) form long after UV exposure in a melanin-dependent manner.

  • Major finding: Most cyclobutane-pyrimidine dimers (CPD) form long after UV exposure in a melanin-dependent manner.

  • Concept: UV-induced reactive species excite melanin to a state with the energy of a UV photon, which can induce CPDs.

  • Impact: Blockade of “dark CPD” formation by melanin chemiexcitation may reduce levels of UV-induced DNA damage.

UV radiation generates DNA photoproducts called cyclobutane-pyrimidine dimers (CPD) that form almost instantaneously after exposure when a UV photon is directly absorbed by cytosine or thymidine. However, Premi and colleagues made the unexpected observation that melanin pigment–containing melanocytes, but not albino melanocytes, were capable of continuously generating CPDs for several hours after UV exposure ended. These “dark CPDs” accounted for half of all CPDs generated after UV exposure and included cytosine-containing CPDs that underlie UV-signature cytosine-to-thymidine mutations. Reactive oxygen and nitrogen species were required for dark CPD production in melanocytes, with UV exposure promoting the creation of superoxide and nitric oxide to form peroxynitrite, a powerful oxidant capable of exciting electrons to a triplet state with the same high energy of a UV photon. Because triplet states can discharge energy through luminescence, the authors monitored melanocytes for luminescence and found that UV irradiation generated luminescence only in melanin-containing cells. Dark CPD production was triplet state–dependent, and peroxynitrite could create a triplet state in melanin itself, which could then create CPDs in the absence of UV in a cell-free system. Although melanin is cytoplasmic, exposure to UV or peroxynitrite led to rapid solubilization and degradation of melanin polymer into monomers, which are lipophilic and potentially capable of entering the nucleus. Consistent with this possibility, pigmented granules could be observed in the nuclei of melanin-containing, but not albino, melanocytes only after UV exposure. Although further characterization of the process of melanin chemiexcitation is needed, these findings suggest that UV-induced DNA damage can be created long after UV exposure ceases and raise the possibility that interference with melanin chemiexcitation and subsequent dark CPD formation could represent a skin cancer prevention strategy.

Premi S, Wallisch S, Mano CM, Weiner AB, Bacchiocchi A, Wakamatsu K, et al. Chemiexcitation of melanin derivatives induces DNA photoproducts long after UV exposure. Science 2015;347:842–7.

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