TETenzymes

TET enzymes, or Ten-Eleven Translocation enzymes, are a family of Fe(II)/α-ketoglutarate-dependent dioxygenases that catalyze the oxidation of 5-methylcytosine (5mC) in DNA to 5-hydroxymethylcytosine (5hmC), and further to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). These oxidation steps are central to dynamic DNA demethylation and epigenetic regulation.

In mammals, the TET family comprises TET1, TET2, and TET3. They exhibit distinct tissue distribution and developmental roles, with TET1 and TET3 often linked to embryonic and neural contexts, and TET2 widely expressed in hematopoietic cells. All three share a catalytic core that coordinates Fe2+ and α-ketoglutarate within a double-stranded β-helix fold.

The oxidized cytosine products can be removed by base excision repair via thymine-DNA glycosylase (TDG) or can be diluted through DNA replication, yielding active DNA demethylation. Notably, 5hmC itself also serves as an epigenetic mark, especially enriched in brain tissue, indicating regulatory roles beyond demethylation.

TET activity is influenced by cellular metabolism and signaling, including the availability of α-ketoglutarate, Fe2+, and ascorbate. Oncometabolites such as 2-hydroxyglutarate, produced by mutant IDH enzymes, can inhibit TET function and affect epigenetic states.

Mutations or reduced function of TET enzymes, particularly TET2, are associated with cancers such as myeloid malignancies, and altered 5hmC patterns are observed in various diseases. Research continues on TETs as biomarkers and potential therapeutic targets, with emphasis on their roles in development, differentiation, and epigenetic regulation.