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Seminars and Colloquia


Shedding light on dark side of the melanin: UV-signature DNA damage without UV 
Wed, Feb 22, 2017,   04:00 PM to 05:00 PM at Seminar Room 34, 2nd Floor, Main Building

Dr. Sanjay Premi
Yale University School of Medicine, USA

Cyclobutane pyrimidine dimers (CPD) are created nearly instantaneously as the energy of a UV photon is absorbed by DNA. Skin cancers like melanoma are etiologically associated with CPD generated by sunlight exposure. Melanin acts as shield for sunlight's UV; however UVA irradiated mice develop melanoma only if their melanocytes contain melanin. To investigate this paradox, we studied repair of UV induced CPD in human and mouse melanocytes. Surprisingly, CPD were created in melanin-containing melanocytes for hours after an initial UV exposure. The same was true for keratinocytes in vivo that received the melanin from melanocytes. These “delayed” or “dark” CPD also included cytosine-containing CPD which initiate UV-signature C®T mutations. In vivo, the skin from mice with yellow fur showed even higher accumulation of dark CPD compared to skin from mice with black fur. Knocking down Xpc and Xpa transcripts revealed the dark CPD which were masked by excision repair in primary human melanocytes from some donors. We identified a novel pathway whereby reactive oxygen and nitrogen species oxidize UV-fragmented melanin and generate a melanin carbonyl in a triplet quantum state. This melanin carbonyl contains energy equivalent to a UV photon and generates CPD by radiationless energy transfer to DNA. This result suggests that melanin is carcinogenic as well as protective against cancer. It also validates the importance of chemically excited species in mammalian biology. Currently, we are screening for novel triplet quenchers to develop "evening-after" sunscreens that could potentially prevent the carcinogenic processes transpiring in skin hours after sun exposure ends. We are also exploring the pathogenicity of this pathway in cancer biology, non-melanoma skin pathologies, and neurodegenration in Parkinsons’s and Alzheimer’s disease.