Posted May 13, 2015
Douglas Brash, Ph.D., and Ruth Halaban, Ph.D., Yale University
Melanomas arise from melanocytes, the cells that synthesize the melanin pigment that gives skin and hair their color. With funding from a PRCRP 2009 Collaborative Translational Science Award, Dr. Brash and his team at Yale University wanted to know whether melanin could contribute to the generation of melanoma. Recent studies in cancer models have found that melanin is necessary for the development of melanoma after ultraviolet light (UV) exposure (particularly UVA), and that melanoma can develop in models predisposed to the disease even without UV exposure due to the presence of a certain type of melanin1,2.
Melanin polymers are effective absorbers of UV light, letting them protect the skin against sunlight. However, Dr. Brash and his team found that melanin contributes to DNA damage in the absence of direct UV exposure. The properties of melanin which make it a good UV absorber also make it susceptible to chemical reactions that, in the end, have potentially harmful results similar to overexposure to UV radiation. Using biochemistry, photochemistry, and excited-state chemistry, Dr. Brash's group was able to determine the chemical pathway.
The group found that UV exposure activates two enzymes, inducible nitric oxide synthase and NADPH oxidase, leading to increases in the free radicals nitric oxide and superoxide. These create peroxynitrite, a powerful oxidant. Peroxynitrite then degrades melanin polymers to melanin fragments. Through a series of chemical reactions, it also excites an electron in a melanin fragment to a quantum triplet state that has the energy of a UV photon. If this fragment is in the vicinity of the cell's DNA, Dr. Brash and his team observed that this quantum triplet state can directly induce the formation of cyclobutane pyrimidine dimers (CPDs), the specific type of DNA damage associated with sunlight-induced melanoma, via energy transfer to DNA in a radiation-independent manner. Surprisingly, the formation of CPDs is detected even hours after UV exposure has ended.
Thus, UV light contributes to damaged DNA hours after exposure, and melanin is an active participant in forming the type of DNA damage that can lead to melanoma. This apparently paradoxical finding results from the underlying chemistry of this phenomenon - the chemical excitation of electrons, termed "chemiexcitation." Chemiexcitation was previously encountered only in bacteria and lower animals, and the research by the Brash lab is the first to document this phenomenon in mammals. Chemically induced electron excitation in bacteria and lower animals has been studied in the context of their bioluminescent properties, such as the flicker in a firefly or the glow of deep sea jellyfish. However, in the context of DNA damage, Dr. Brash explains that chemiexcitation can instead result in energy transfer from a high energy state electron to DNA. Once the energy is in the DNA, it behaves the same as if the UV insult was direct, that is, by forming CPDs. Luckily, most CPDs are caught and repaired; however, errors in this process are the early stages of carcinogenesis that lead to melanoma.
The findings of the Brash lab have many significant clinical implications, the most important of which is that the amount of DNA damage from UV exposure has been underestimated. But the slowness of the process also means that these events can be blocked by a new generation of sunscreens and aftersun care. By uncovering a new mechanism of melanin-dependent DNA damage, Dr. Brash and his colleagues have found evidence that melanin may be carcinogenic as well as protective against cancer. Dr. Brash wants people to know that skin cancer is still lower for people with melanin in their skin than for those without it. "It seems contradictory for melanin to be both helpful and harmful," he says, but, "it seems to be a compromise - the best that nature could do."
Premi S, Wallisch S, Mano CM, et al. 2015. Chemiexcitation of melanin derivatives induces DNA photoproducts long after UV exposure. Science 347:842-847.
Mitra D, Luo X, Morgan A, et al. 2012. An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background. Nature 491:449-453.
Noonan FP, Zaidi MR, Wolnicka Glubisz A, et al. 2012. Melanoma induction by ultraviolet A but not ultraviolet B radiation requires melanin pigment. Nat Commun 3:884.