Ten-Eleven Translocation methylcytosine dioxygenase (TET) (TET)

Ten-Eleven Translocation (TET) enzymes, comprising TET1, TET2, and TET3, are Fe(II)- and alpha-ketoglutarate-dependent dioxygenases that serve as critical epigenetic regulators by initiating active DNA demethylation [1, 4]. They catalyze the sequential oxidation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-fC), and 5-carboxylcytosine (5-caC), effectively erasing repressive methylation marks to modulate gene expression [6, 8]. These enzymes are essential for maintaining stem cell pluripotency and guiding hematopoietic and neuronal differentiation during development [9, 20]. Mutations in TET genes, particularly TET2, are frequently observed in hematological malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), where loss of function leads to DNA hypermethylation and malignant transformation [11, 14]. Therapeutic interest focuses on both inhibitors for specific oncogenic contexts and activators, such as Vitamin C, which can restore enzymatic activity in certain TET-deficient cells [10, 16, 17]. Furthermore, TET activity is sensitive to metabolic changes, as it can be competitively inhibited by oncometabolites like 2-hydroxyglutarate in IDH-mutant cancers [14, 19].

Other names

TET familyTET1TET2TET3Methylcytosine dioxygenaseCXXC finger protein 6LCX

TET enzymes catalyze the oxidation of 5-mC using molecular oxygen, Fe(II), and alpha-ketoglutarate (a-KG) as co-factors; therapeutic agents act by either supplementing these co-factors to restore activity or competitively inhibiting the a-KG binding site to reduce global or locus-specific DNA demethylation.