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1	Enhanced DNA binding capacity on up-regulated epidermal wild-type p53 in vitiligo by H2O2-mediated oxidation: a possible repair mechanism for DNA damage Salem, Mohamed M.A., Shalbaf, Mohammad, Gibbons, Nick C., Chavan, Bhavan, Thornton, M. Julie, Schallreuter, Karin U. January 2009 (has links) Vitiligo is characterized by a patchy loss of inherited skin color affecting approximately 0.5% of individuals of all races. Despite the absence of the protecting pigment and the overwhelming evidence for hydrogen peroxide (H(2)O(2))-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 polymerasebeta 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(-) (300 x 10(-6) M) abrogates DNA binding, while H(2)O(2)-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. Adult Apoptosis; Physiology Ataxia Telangiectasia Mutated Proteins Caspase 3; Biosynthesis Cell cycle proteins; Metabolism Cytochromes c DNA DNA damage; Drug effects DNA repair DNA-binding proteins Electrophoretic mobility shift assay Epidermis Guanosine; Analogs & derivatives Humans Hydrogen peroxide; Pharmacology Middle aged Oxidation-reduction Oxidative stress Peroxynitrous acid Protein-Serine-Threonine Kinases Proto-Oncogene Proteins c-bcl-2 Proto-Oncogene Proteins c-mdm2 Tumor Suppressor Protein p53 Tumor Suppressor Proteins Up-Regulation Vitiligo p300-CBP Transcription Factors REF 2014

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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