TET enzymes (TET1/2/3)

TET1, TET2 and TET3 are Fe(II)- and alpha-ketoglutarate-dependent dioxygenases that catalyse stepwise oxidation of 5-methylcytosine (5mC) on DNA to 5-hydroxymethylcytosine (5hmC), then 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). These oxidised bases can be excised by thymine DNA glycosylase and replaced via base excision repair, providing one route to active DNA demethylation. TET activity is sensitive to oxygen, vitamin C and TCA-cycle intermediates, linking the enzymes to cellular metabolism. Loss-of-function somatic mutations in TET2 are among the most frequent drivers of clonal haematopoiesis of indeterminate potential (CHIP), an age-associated expansion of mutant blood cell clones that is linked to increased risks of haematological malignancy, cardiovascular disease and all-cause mortality.