Rewriting the script: The story of vitamin C and the epigenome

Abstract

Vitamin C is a vital micronutrient in the maintenance of numerous cellular functions and the development of mammalian systems. Vitamin C predominantly exists physiologically as the ascorbate anion, an antioxidant classically linked to the prevention of scurvy. Current research has shown that ascorbate plays an additional role critical in DNA demethylation by acting as a cofactor for the teneleven translocation (TET) family of methylcytosine dioxygenase enzymes. TET enzymes hydroxylate 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), an epigenetic marker whose further processing results in cleavage of the methylated cytosine and subsequent repair via the base excision repair pathway, resulting in completion of active DNA demethylation. Recent work has also speculated ascorbate's role in mediating histone demethylation dynamics via Jumonji C domain (JmjC) demethylase enzymes belonging to the same enzyme family as TET dioxygenases. Although these roles in demethylation are of principal importance, the need for ascorbate initially evolved in early photosynthetic eukaryotes who required a reducing agent to protect themselves from photodamage generated by the chloroplast, a role that ultimately affected the evolutionary paths of insects and herbivorous animals. Altogether, the widereaching functions of ascorbate play a critical role in the maintenance of mammalian demethylation dynamics and organismal development.