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Enhanced DNA binding capacity on up-regulated epidermal wild-type p53 in vitiligo by H₂O₂-mediated oxidation: a possible repair mechanism for DNA damage

Mohamed M. A. E. L. Salem^*,1, Mohammad Shalbaf^*,1, Nicholas C. J. Gibbons^*,, Bhaven Chavan^*, J. M. Thornton^* and Karin U. Schallreuter^*,,2

^* Clinical and Experimental Dermatology, Department of Biomedical Sciences/Centre for Skin Sciences, School of Life Sciences, University of Bradford, Bradford, UK; and

Institute for Pigmentary Disorders, in association with E. M. Arndt University, Greifswald, Germany, and University of Bradford, Bradford, UK

² Correspondence: Clinical and Experimental Dermatology, Centre for Skin Sciences, School of Life Sciences, University of Bradford, Bradford, BD7 1DP, UK. E-mail: k.schallreuter{at}bradford.ac.uk

Vitiligo is characterized by a patchy loss of inherited skin color affecting 0.5% of individuals of all races. Despite the absence of the protecting pigment and the overwhelming evidence for hydrogen peroxide (H₂O₂)-induced oxidative stress in the entire epidermis of these patients, there is neither increased photodamage/skin aging nor a higher incidence for sun-induced nonmelanoma skin cancer. Here we demonstrate for the first time increased DNA damage via 8-oxoguanine in the skin and plasma in association with epidermal up-regulated phosphorylated/acetylated p53 and high levels of the p53 antagonist p76^MDM2. Short-patch base-excision repair via hOgg1, APE1, and polymeraseβ DNA repair is up-regulated. Overexpression of Bcl-2 and low caspase 3 and cytochrome c levels argue against increased apoptosis in this disease. Moreover, we show the presence of high epidermal peroxynitrite (ONOO^–) levels via nitrotyrosine together with high nitrated p53 levels. We demonstrate by EMSA that nitration of p53 by ONOO^– (300x10^–6 M) abrogates DNA binding, while H₂O₂-oxidized p53 (10^–3 M) enhances DNA binding capacity and prevents ONOO^–-induced abrogation of DNA binding. Taken together, we add a novel reactive oxygen species to the list of oxidative stress inducers in vitiligo. Moreover, we propose up-regulated wild-type p53 together with p76^MDM2 as major players in the control of DNA damage/repair and prevention of photodamage and nonmelanoma skin cancer in vitiligo.—Salem, M. M. A. E. L., Shalbaf, M., Gibbons, N. C. J., Chavan, B., Thornton, J. M., Schallreuter, K. U. Enhanced DNA binding capacity on up-regulated epidermal wild-type p53 in vitiligo by H₂O₂-mediated oxidation: a possible repair mechanism for DNA damage.

Key Words: peroxynitrite • catalase • 8-oxoG • p76^MDM2 • cell cycle arrest • skin cancer • apoptosis