TET1 Recombinant Protein

Function: Dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in active DNA demethylation. Also mediates subsequent conversion of 5hmC into 5-formylcytosine (5fC), and conversion of 5fC to 5-carboxylcytosine (5caC). Conversion of 5mC into 5hmC, 5fC and 5caC probably constitutes the first step in cytosine demethylation. Methylation at the C5 position of cytosine bases is an epigenetic modification of the mammalian genome which plays an important role in transcriptional regulation. In addition to its role in DNA demethylation, plays a more general role in chromatin regulation. Preferentially binds to CpG-rich sequences at promoters of both transcriptionally active and Polycomb-repressed genes. Involved in the recruitment of the O-GlcNAc transferase OGT to CpG-rich transcription start sites of active genes, thereby promoting histone H2B GlcNAcylation by OGT. Also involved in transcription repression of a subset of genes through recruitment of transcriptional repressors to promoters. Involved in the balance between pluripotency and lineage commitment of cells it plays a role in embryonic stem cells maintenance and inner cell mass cell specification. Ref.1 Ref.7 Ref.8 Ref.9 Ref.11

Catalytic activity: DNA 5-methylcytosine + 2-oxoglutarate + O2 = DNA 5-hydroxymethylcytosine + succinate + CO2. Ref.8 Ref.9DNA 5-hydroxymethylcytosine + 2-oxoglutarate + O2 = DNA 5-formylcytosine + succinate + CO2. Ref.8 Ref.9DNA 5-formylcytosine + 2-oxoglutarate + O2 = DNA 5-carboxylcytosine + succinate + CO2. Ref.8 Ref.9

Cofactor: Binds 1 Fe2+ ion per subunit. Ref.8

Subunit structure: Interacts with HCFC1 and OGT

By similarity. Interacts with SIN3A; recruits the transcriptional corepressor SIN3A to gene promoters. Ref.10

Subcellular location: Nucleus

Probable.

Tissue specificity: Expressed in fetal heart, lung and brain, and in adult skeletal muscle, thymus and ovary. Not detected in adult heart, lung or brain. Ref.1 Ref.6

Post-translational modification: Glycosylated. Interaction with OGT leads to GlcNAcylation

By similarity.

Involvement in disease: A chromosomal aberration involving TET1 may be a cause of acute leukemias. Translocation t(10;11)(q22;q23) with KMT2A/MLL1. This is a rare chromosomal translocation 5' KMT2A/MLL1-TET1 3'.

Sequence similarities: Belongs to the TET family.Contains 1 CXXC-type zinc finger.

Caution: Subsequent steps in cytosine demethylation are subject to discussion. According to a first model cytosine demethylation occurs through deamination of 5hmC into 5-hydroxymethyluracil (5hmU) and subsequent replacement by unmethylated cytosine by the base excision repair system (Ref.9). According to another model, cytosine demethylation is rather mediated via conversion of 5hmC into 5fC and 5caC, followed by excision by TDG and replacement by unmethylated cytosine.

Sequence caution: The sequence CAD28467.3 differs from that shown. Reason: Contaminating sequence. Potential poly-A sequence.