Ascorbic Acid Enhances Tet-Mediated 5-Methylcytosine Oxidation and Promotes DNA Demethylation in Mammals
| العنوان: | Ascorbic Acid Enhances Tet-Mediated 5-Methylcytosine Oxidation and Promotes DNA Demethylation in Mammals |
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| المؤلفون: | Hua Huang, Weikuan Gu, Danni Wu, Juan Gao, Guoliang Xu, Bailin Zhao, Zheng Li, Hailin Wang, Ying Yang, Zechen Chong, Shi-Qing Mao, Chao Zhao, Ruichuan Yin, Cuiping Li, Yun-Gui Yang, Yan Jiao, Shengquan Liu, Dapeng Zhang |
| المصدر: | Journal of the American Chemical Society. 135:10396-10403 |
| بيانات النشر: | American Chemical Society (ACS), 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | DNA Hydroxymethylation, Ascorbic Acid, Biochemistry, Catalysis, Cofactor, Dioxygenases, Mice, chemistry.chemical_compound, Colloid and Surface Chemistry, Proto-Oncogene Proteins, Animals, 5-Hydroxymethylcytosine, chemistry.chemical_classification, biology, Chemistry, DNA, General Chemistry, Methylation, DNA Methylation, Ascorbic acid, DNA-Binding Proteins, 5-Methylcytosine, DNA demethylation, Enzyme, biology.protein, Oxidation-Reduction |
| الوصف: | DNA hydroxymethylation and its mediated DNA demethylation are critical for multiple cellular processes, for example, nuclear reprogramming, embryonic development, and many diseases. Here, we demonstrate that a vital nutrient ascorbic acid (AA), or vitamin C (Vc), can directly enhance the catalytic activity of Tet dioxygenases for the oxidation of 5-methylcytosine (5mC). As evidenced by changes in intrinsic fluorescence and catalytic activity of Tet2 protein caused by AA and its oxidation-resistant derivatives, we further show that AA can uniquely interact with the C-terminal catalytic domain of Tet enzymes, which probably promotes their folding and/or recycling of the cofactor Fe(2+). Other strong reducing chemicals do not have a similar effect. These results suggest that AA also acts as a cofactor of Tet enzymes. In mouse embryonic stem cells, AA significantly increases the levels of all 5mC oxidation products, particularly 5-formylcytosine and 5-carboxylcytosine (by more than an order of magnitude), leading to a global loss of 5mC (∼40%). In cells deleted of the Tet1 and Tet2 genes, AA alters neither 5mC oxidation nor the overall level of 5mC. The AA effects are however restored when Tet2 is re-expressed in the Tet-deficient cells. The enhancing effects of AA on 5mC oxidation and DNA demethylation are also observed in a mouse model deficient in AA synthesis. Our data establish a direct link among AA, Tet, and DNA methylation, thus revealing a role of AA in the regulation of DNA modifications. |
| تدمد: | 1520-5126 0002-7863 |
| DOI: | 10.1021/ja4028346 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c35f75ce73d973219d98926b9f7776a1 https://doi.org/10.1021/ja4028346 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c35f75ce73d973219d98926b9f7776a1 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15205126 00027863 |
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| DOI: | 10.1021/ja4028346 |