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TET Enzymes

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]

TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.

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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.[2] 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. However, 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). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.[3] Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.[3]

Function

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).[4] Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.[4] While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.[4][5]

Disease

Relevance

Structural highlights

References

  1. ↑ Lorsbach RB, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR. TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23). Leukemia. 2003 Mar;17(3):637-41. PMID:12646957 doi:http://dx.doi.org/10.1038/sj.leu.2402834
  2. ↑ 2.0 2.1 Kinney SR, Pradhan S. Ten eleven translocation enzymes and 5-hydroxymethylation in mammalian development and cancer. Adv Exp Med Biol. 2013;754:57-79. doi: 10.1007/978-1-4419-9967-2_3. PMID:22956496 doi:http://dx.doi.org/10.1007/978-1-4419-9967-2_3
  3. ↑ 3.0 3.1 Frauer C, Rottach A, Meilinger D, Bultmann S, Fellinger K, Hasenoder S, Wang M, Qin W, Soding J, Spada F, Leonhardt H. Different binding properties and function of CXXC zinc finger domains in Dnmt1 and Tet1. PLoS One. 2011 Feb 2;6(2):e16627. doi: 10.1371/journal.pone.0016627. PMID:21311766 doi:http://dx.doi.org/10.1371/journal.pone.0016627
  4. ↑ 4.0 4.1 4.2 He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q, Ding J, Jia Y, Chen Z, Li L, Sun Y, Li X, Dai Q, Song CX, Zhang K, He C, Xu GL. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science. 2011 Sep 2;333(6047):1303-7. doi: 10.1126/science.1210944. Epub 2011 Aug, 4. PMID:21817016 doi:http://dx.doi.org/10.1126/science.1210944
  5. ↑ Kohli RM, Zhang Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature. 2013 Oct 24;502(7472):472-9. doi: 10.1038/nature12750. PMID:24153300 doi:http://dx.doi.org/10.1038/nature12750

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Madelyn Kasprzak

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