TET enzymes are a family of dioxygenases that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the Mixed Lineage Leukemia (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). [1]
Structure
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.[2] The DSBH domain contains three Fe2+ binding sites and an α-ketoglutarate binding site. This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases. In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. The TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). Evidence suggests that the KFGG motif increases affinity for unmethylated DNA [1]. While TET1 still prefers unmethylated CpGs in DNA over methylated CpGs with an approximate ratio of 3 : 1, this is much less than DNMT1’s ratio of 48 to 1 in its preference for unmethylated CpGs over methylated CpGs [2]. This agrees with the fact that DNMTs methylate DNA whereas TET enzymes are suspected to be agents in active DNA demethylation, specifically cytosine.
Function
Disease
Relevance
Structural highlights
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