Figure 4.

Under normal conditions, TET2 utilizes a-KG as a substrate to hydroxylate 5-methylcytosine (5mc) to 5-hydroxymethylcytosine (5hmc) during DNA demethylation. a-KG also binds to the JmjC domain of histone demethylases, which function to demethylate lysine residues on histone tails and subsequently regulate gene transcriptional activity. R-2-HG produced by the mutant IDH1 protein acts as a competitive inhibitor of TET2 and JmjC, promoting a hypermethylator phenotype that maintains an undifferentiated tumor state.