Figure 1.
Reactions involved in TET-mediated oxidation of 5-methylcytosine (5-mC). Depicted here is cytosine-mediated methylation by the family of DNA methyltransferases (DNMT) with the substrate S-adenosyl methionine (SAM) leading to the formation of 5-mC. TET family members are then capable of mediating the iterative oxidation of 5-mC to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-fC), and 5-carboxylcytosine (5-caC) in an Fe(II), O2, and α-ketoglutarate (α-KG)-dependent reaction. These α-KG-dependent reactions can be inhibited by the oncometabolite 2-hydroxyglutarate (2-HG), which is a neomorphic by-product of mutant IDH1 and IDH2. Each downstream product (5-hmC, 5-fC, and 5-caC) can serve as substrates for thymine DNA glycosylase (TDG) leading to base excision repair (BER) and eventual return to unmodified cytosine.