Ten-eleven translocation methylcytosine dioxygenase (TET)

Ten-eleven translocation (TET) methylcytosine dioxygenases are a family of three enzymes (TET1, TET2, and TET3) that play a critical role in the epigenetic regulation of the genome by mediating DNA demethylation (UniProt, 2024). These enzymes are Fe(II)- and alpha-ketoglutarate-dependent dioxygenases that oxidize 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and further oxidation products, which are intermediates in the removal of methyl groups from DNA (PubMed, 2016). TET2, in particular, is frequently mutated in hematological malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), where loss of function leads to DNA hypermethylation and impaired hematopoietic differentiation (NIH, 2023). Therapeutic strategies often focus on restoring TET activity, for instance through high-dose Vitamin C supplementation, which acts as a cofactor to enhance TET function, or by inhibiting the production of oncometabolites like 2-hydroxyglutarate that competitively inhibit TET enzymes (Cimmino et al., 2017). Understanding the balance of TET activity is essential for developing targeted epigenetic therapies in oncology and regenerative medicine (PubMed, 2020).

Other names

TET familyMethylcytosine dioxygenaseDNA demethylaseCXXC-type zinc finger protein (UniProt, 2024)

TET enzymes catalyze the sequential oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) using oxygen and alpha-ketoglutarate as co-substrates and Fe(II) as a cofactor (UniProt, 2024). This process initiates the active DNA demethylation pathway, where 5fC and 5caC are subsequently removed by thymine DNA glycosylase (TDG) and replaced with unmethylated cytosine via base excision repair (PubMed, 2016). By regulating the methylation status of CpG islands in promoter regions, TET enzymes directly influence gene expression and cellular identity (PubMed, 2017).