Antioxidant protein TR1 is critical for normal melanocyte function and protect melanocytes from UVB-induced DNA damage in vivo Evan L. Carpenter1, Gitali Ganguli-Indra1,2, Pamela Cassidy2,3, Gary Merrill4, Arup K. Indra1,2,3,4,5 1Department of Pharmaceutical Sciences, OSU-OHSU College of Pharmacy, Corvallis, OR; 2Knight Cancer Institute, OHSU, Portland, OR; 3Department of Dermatology, Oregon Health & Science University (OHSU), Portland, OR; 4Dept. of Biochemistry & Biophysics, OSU, Corvallis, OR; 5Linus Pauling Institute, OSU, Corvallis, OR, USA Melanoma is the deadliest skin cancer and the leading cause of death due to skin disease. While melanoma is treatable during early progression, once metastasis and spread has occurred the rate of survival rapidly declines. Therefore, a better understanding of the multitude of factors that lead to disease progression and metastasis is needed for more effective treatment. Oxidative stress is a major contributing factor in cancer progression and expression of antioxidant protein thioredoxin reductase 1 (TR1) is significantly elevated during melanoma progression indicating a potential role in melanoma-genesis. TR1 is a constituent of the thioredoxin antioxidant system, which plays an important role in the cellular antioxidant stress response. Here we seek to better understand the in vivo role of TR1 in melanocyte physiology and in ultraviolet (UV) induced melanomagenesis. To that end, we have generated a knockout mouse model in which Txnrd1 encoding TR1 has been selectively ablated in melanocytes via Cre recombinase driven by the melanocyte specific tyrosinase promoter to generate Tr1mel-/- mice. The mutant mice exhibit a depigmentation phenotype that includes reduced melanin content in the extremities (i.e. ears, paws, and tail) in addition to variable amelanotic ventral fur spotting. The amelanotic ventral spots lack both melanin and melanocytes, suggesting defects during the development of the melanocyte lineage in the absence of TR1. We also subjected the Tr1mel-/- mice to UVB irradiation and have observed a significant reduction in melanocyte density, elevation of DNA damage, and reduction in proliferation early on after UVB exposure. Altogether, above data suggest that TR1 is necessary for normal melanocyte function and melanin synthesis during development and likely plays a role in preventing UV-induced melanomagenesis.