¶ Overview
Tet1 Protein is involved in cellular processes relevant to neurodegeneration. For detailed information, refer to the References section.
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title: Tet Methylcytosine Dioxygenase 1 Protein [2]
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- Protein Name: Tet Methylcytosine Dioxygenase 1 Protein
- Gene: TET1
- UniProt: Q8NFU7
- PDB: 6VN6, 6VN7
- Molecular Weight: 235 kDa
- Subcellular Localization: Nucleus
- Protein Family: TET family (2-oxoglutarate-dependent dioxygenases)
¶ Summary
TET1 is a 2-oxoglutarate-dependent dioxygenase that catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). This is the first step in active DNA demethylation and is crucial for epigenetic regulation during development and in disease. [7]
¶ Structure
TET1 contains an N-terminal CXXC DNA binding domain that targets it to CpG-rich promoter regions. The catalytic domain is in the C-terminus and contains the 2-oxoglutarate (2-OG) binding motif and Fe(II) binding residues. The CXXC domain is evolutionarily conserved and binds unmethylated DNA.
The catalytic mechanism involves Fe(II)-catalyzed oxidation of 5mC to 5hmC using 2-OG and oxygen as co-substrates, releasing CO2 and succinate.
¶ Normal Function
TET1 catalyzes the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine. This reaction is the initiating step in active DNA demethylation, as 5hmC can be further oxidized to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which can be excised by TDG or other base excision repair glycosylases.
TET1 is highly expressed in embryonic stem cells and is essential for pluripotency. In the brain, 5hmC is abundant in neurons where it marks active gene promoters and enhancers. TET1 regulates learning and memory through activity-dependent demethylation of plasticity genes.
¶ Role in Disease
Rett Syndrome: While MECP2 is the primary cause, TET1 dysregulation contributes to the Rett phenotype. Reduced 5hmC levels are observed in Rett syndrome brains, affecting genes critical for neuronal function.
Alzheimer Disease: TET1 expression and 5hmC levels are altered in AD brains. TET1-mediated demethylation affects genes involved in amyloid processing and tau phosphorylation.
Intellectual Disability: TET1 mutations are associated with neurodevelopmental disorders with intellectual disability and speech delay.
¶ Therapeutic Targeting
Small Molecule Inhibitors: No specific TET1 inhibitors are in clinical use, but 2-OG analogs can inhibit TET activity.
Therapeutic Potential: Enhancing TET1 activity may have therapeutic benefits in neurodegenerative diseases by promoting DNA demethylation of neuroprotective genes.
¶ Key Publications
- Kriaucionis S et al., 5-hydroxymethylcytosine in the mammalian brain (2009)
- Zhang RR et al., TET1 regulates adult hippocampal neurogenesis (2013)
- Ito S et al., TET1 catalytic mechanism (2010)
¶ Cross-Links
¶ See Also
- Neurodegeneration — General mechanisms
¶ External Links
¶ References
¶ Additional references
Ito et al. TET proteins in DNA demethylation (2010). 2010. ↩︎
Zhang et al. TET1 in Alzheimer's disease (2018). 2018. ↩︎
Chen et al. TET enzymes in neurodegeneration (2019). 2019. ↩︎
Li et al. 5hmC in brain aging (2017). 2017. ↩︎
Song et al. TET-mediated DNA oxidation in neurons (2013). 2013. ↩︎
Costa and Wolff, TET proteins and cognitive function (2016). 2016. ↩︎