Ascorbic Acid Reprograms Epigenome and Epitranscriptome by Reducing Fe(III) in the Catalytic Cycle of Dioxygenases

作者：Weizhi He, Xiaotong Yin, Chu Xu, Xiangyue Liu, Yue Huang, Cai‐Guang Yang, Yanhui Xu, Lulu Hu · 发表于：ACS Chemical Biology · 年份：2023 · DOI：10.1021/acschembio.3c00567 · 被引用次数：10 · 研究领域：RNA modifications and cancer、Epigenetics and DNA Methylation、Cancer-related gene regulation

Ascorbic acid (ASC) has been reported to stimulate DNA iterative oxidase ten-eleven translocation (TET) enzymes, Jumonji C-domain-containing histone demethylases, and potentially RNA m 6 A demethylases FTO and ALKBH5 as a cofactor. Although ascorbic acid has been widely investigated in reprogramming DNA and histone methylation status in vitro, in cultured cells and mouse models, its specific role in the catalytic cycle of dioxygenases remains enigmatic. Here, we systematically investigated the stimulation of ASC toward TET2, ALKBH3, histone demethylases, and FTO. We find that ASC reprograms epitranscriptome by erasing the hypermethylated m 6 A sites in mRNA. Biochemistry and electron spin resonance assays demonstrate that ASC enters the active pocket of dioxygenases and reduces Fe(III), either incorporated upon protein synthesis or generated upon rebounding the hydroxyl radical during oxidation, into Fe(II). Finally, we propose a remedied model for the catalytic cycle of dioxygenases by adding in the essential cofactor, ASC, which refreshes and regenerates inactive dioxygenase through recycling Fe(III) into Fe(II) in a dynamic “hit-and-run” manner.