The DNA methylation and demethylation pathway, and effect of TET2 and IDH1/2 mutations on epigenetic DNA and histone modifications. (A) The DNMT family of DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) each may place a methyl group on the C5 position of DNA cytosine residues in a reaction which requires SAM as a cofactor. (B) Members of the TET family of enzymes (TET1, TET2, TET3) may then oxidize 5-mC to 5hmC an enzymatic reaction which requires Fe(II) and α-KG as substrates. The TET family may also then iteratively oxidize 5hmC further to 5-formylcytosine followed by 5-caC. 5-caC can be directly recognized by the enzyme TDG followed by excision with the BER pathway (an enzymatic activity that is unable to excise 5hmC or 5-mC) to generate unmethylated cytosine. The AID-APOBEC DNA repair pathway can also convert 5hmC to 5-hydroxymethyluracil which activates the BER using TDG or the SMUG1 to generate unmethylated cytosines. TET-mediated enzymatic processes are dependent on α-KG. The presence of an IDH1/2 mutation results in the production of 2-HG, which is structurally very similar to α-KG and can compete with α-KG to inhibit α-KG–dependent enzymatic processes. This includes inhibition of the α-KG–dependent family of JMJC containing histone demethylases. JMJC histone demethylases are responsible for demethylation of histone ³H residues at amino acid residues 2, 4, 9, 27, and 36 and histone H4 amino acid residue 3. 5-cac, 5-carboxylcytosine; AID, activation-induced cytidine deaminase; APOBEC, apolipoprotein B mRNA editing enzyme catalytic; BER, base-excision repair; SMUG1, single-strand-selective monofunctional uracil DNA glycosylase; TDG, thymine DNA glycosylase.