A double-stranded beta helix (DSBH) fold domain of the 2-oxoglutarate (2OG)-Fe(II)-dependent dioxygenase (2OGFeDO) superfamily found in various eukaryotes, bacteria and bacteriophages (PMID:19411852). Members of this family catalyze nucleic acid modifications, such as thymidine hydroxylation during base J synthesis in kinetoplastids (PMID:20215442) and the conversion of 5 methyl-cytosine (5-mC) to 5-hydroxymethyl-cytosine (hmC) (PMID:19372391) or further oxidation to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) (PMID:21817016). Metazoan TET proteins contain a cysteine-rich region inserted into the core of the DSBH fold. Vertebrate TET proteins are oncogenes that are mutated in various myeloid cancers (PMID:21057493). Fungal and algal versions of this family are linked to a predicted transposase and show lineage-specific expansions (PMID:19411852).
This entry represents the catalytic domain from nucleic-acid modifying members of the 2-oxoglutarate (2OG)-Fe(II)-dependent dioxygenase (2OGFeDO) superfamily [ (PUBMED:19411852) ]. These proteins catalyze nucleic acid modifications, such as thymidine hydroxylation during base J synthesis in kinetoplastids [ (PUBMED:20215442) ], and the conversion of 5 methyl-cytosine (5-mC) to 5-hydroxymethyl-cytosine (hmC) [ (PUBMED:19372391) ], or further oxidation to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) [ (PUBMED:21817016) ]. Metazoan TET proteins contain a cysteine-rich region inserted into the core of the DSBH fold. Vertebrate TET proteins are oncogenes that are mutated in various myeloid cancers [ (PUBMED:21057493) ]. Fungal and algal versions of this family are linked to a predicted transposase and show lineage-specific expansions [ (PUBMED:19411852) ].
Family alignment:
There are 1357 Tet_JBP domains in 1357 proteins in SMART's nrdb database.
Click on the following links for more information.
Evolution (species in which this domain is found)
Taxonomic distribution of proteins containing Tet_JBP domain.
This tree includes only several representative species. The complete taxonomic breakdown of all proteins with Tet_JBP domain is also avaliable.
Click on the protein counts, or double click on taxonomic names to display all proteins containing Tet_JBP domain in the selected taxonomic class.
Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalianDNA.
Science. 2011; 333: 1303-7
Display abstract
The prevalent DNA modification in higher organisms is the methylation of cytosineto 5-methylcytosine (5mC), which is partially converted to5-hydroxymethylcytosine (5hmC) by the Tet (ten eleven translocation) family ofdioxygenases. Despite their importance in epigenetic regulation, it is unclearhow these cytosine modifications are reversed. Here, we demonstrate that 5mC and 5hmC in DNA are oxidized to 5-carboxylcytosine (5caC) by Tet dioxygenases invitro and in cultured cells. 5caC is specifically recognized and excised bythymine-DNA glycosylase (TDG). Depletion of TDG in mouse embyronic stem cellsleads to accumulation of 5caC to a readily detectable level. These data suggestthat oxidation of 5mC by Tet proteins followed by TDG-mediated base excision of5caC constitutes a pathway for active DNA demethylation.
Two thymidine hydroxylases differentially regulate the formation of glucosylated DNA at regions flanking polymerase II polycistronic transcription unitsthroughout the genome of Trypanosoma brucei.
Nucleic Acids Res. 2010; 38: 3923-35
Display abstract
Base J is a hypermodified DNA base localized primarily to telomeric regions ofthe genome of Trypanosoma brucei. We have previously characterized twothymidine-hydroxylases (TH), JBP1 and JBP2, which regulate J-biosynthesis. JBP2is a chromatin re-modeling protein that induces de novo J-synthesis, allowingJBP1, a J-DNA binding protein, to stimulate additional J-synthesis. Here, we showthat both JBP2 and JBP1 are capable of stimulating de novo J-synthesis. Welocalized the JBP1- and JBP2-stimulated J by anti-J immunoprecipitation andhigh-throughput sequencing. This genome-wide analysis revealed an enrichment ofbase J at regions flanking polymerase II polycistronic transcription units (PolII PTUs) throughout the T. brucei genome. Chromosome-internal J deposition isprimarily mediated by JBP1, whereas JBP2-stimulated J deposition at the telomericregions. However, the maintenance of J at JBP1-specific regions is dependent onJBP2 SWI/SNF and TH activity. That similar regions of Leishmania major alsocontain base J highlights the functional importance of the modified base at PolII PTUs within members of the kinetoplastid family. The regulation of Jsynthesis/localization by two THs and potential biological function of J inregulating kinetoplastid gene expression is discussed.
Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2.
Nature. 2010; 468: 839-43
Display abstract
TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. The gene encoding TET2 resides atchromosome 4q24, in a region showing recurrent microdeletions and copy-neutralloss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies.Somatic TET2 mutations are frequently observed in myelodysplastic syndromes(MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes includingchronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) andsecondary AML (sAML). We show here that TET2 mutations associated with myeloidmalignancies compromise catalytic activity. Bone marrow samples from patientswith TET2 mutations displayed uniformly low levels of 5hmC in genomic DNAcompared to bone marrow samples from healthy controls. Moreover, small hairpinRNA (shRNA)-mediated depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte/macrophage lineages in culture. There was no significant difference in DNA methylation between bone marrow samples frompatients with high 5hmC versus healthy controls, but samples from patients withlow 5hmC showed hypomethylation relative to controls at the majority ofdifferentially methylated CpG sites. Our results demonstrate that Tet2 isimportant for normal myelopoiesis, and suggest that disruption of TET2 enzymatic activity favours myeloid tumorigenesis. Measurement of 5hmC levels in myeloidmalignancies may prove valuable as a diagnostic and prognostic tool, to tailortherapies and assess responses to anticancer drugs.
Prediction of novel families of enzymes involved in oxidative and other complexmodifications of bases in nucleic acids.
Cell Cycle. 2009; 8: 1698-710
Display abstract
Modified bases in nucleic acids present a layer of information that directsbiological function over and beyond the coding capacity of the conventionalbases. While a large number of modified bases have been identified, many of theenzymes generating them still remain to be discovered. Recently, members of the2-oxoglutarate- and iron(II)-dependent dioxygenase super-family, which modifydiverse substrates from small molecules to biopolymers, were predicted andsubsequently confirmed to catalyze oxidative modification of bases in nucleicacids. Of these, two distinct families, namely the AlkB and the kinetoplastidbase J binding proteins (JBP) catalyze in situ hydroxylation of bases in nucleic acids. Using sensitive computational analysis of sequences, structures andcontextual information from genomic structure and protein domain architectures,we report five distinct families of 2-oxoglutarate- and iron(II)-dependentdioxygenase that we predict to be involved in nucleic acid modifications. Amongthe DNA-modifying families, we show that the dioxygenase domains of thekinetoplastid base J-binding proteins belong to a larger family that includes theTet proteins, prototyped by the human oncogene Tet1, and proteins frombasidiomycete fungi, chlorophyte algae, heterolobosean amoeboflagellates andbacteriophages. We present evidence that some of these proteins are likely to be involved in oxidative modification of the 5-methyl group of cytosine leading tothe formation of 5-hydroxymethylcytosine. The Tet/JBP homologs from basidiomycetefungi such as Laccaria and Coprinopsis show large lineage-specific expansions anda tight linkage with genes encoding a novel and distinct family of predictedtransposases, and a member of the Maelstrom-like HMG family. We propose thatthese fungal members are part of a mobile transposon. To the best of ourknowledge, this is the first report of a eukaryotic transposable element thatencodes its own DNA-modification enzyme with a potential regulatory role. Througha wider analysis of other poorly characterized DNA-modifying enzymes we also showthat the phage Mu Mom-like proteins, which catalyze the N6-carbamoylmethylationof adenines, are also linked to diverse families of bacterial transposases,suggesting that DNA modification by transposable elements might have a moregeneral presence than previously appreciated. Among the other families of2-oxoglutarate- and iron(II)-dependent dioxygenases identified in this study, onewhich is found in algae, is predicted to mainly comprise of RNA-modifying enzymesand shows a striking diversity in protein domain architectures suggesting thepresence of RNA modifications with possibly unique adaptive roles. The resultspresented here are likely to provide the means for future investigation ofunexpected epigenetic modifications, such as hydroxymethyl cytosine, that couldprofoundly impact our understanding of gene regulation and processes such as DNA demethylation.
Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLLpartner TET1.
Science. 2009; 324: 930-5
Display abstract
DNA cytosine methylation is crucial for retrotransposon silencing and mammaliandevelopment. In a computational search for enzymes that could modify5-methylcytosine (5mC), we identified TET proteins as mammalian homologs of thetrypanosome proteins JBP1 and JBP2, which have been proposed to oxidize the5-methyl group of thymine. We show here that TET1, a fusion partner of the MLLgene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependentenzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) incultured cells and in vitro. hmC is present in the genome of mouse embryonic stemcells, and hmC levels decrease upon RNA interference-mediated depletion of TET1. Thus, TET proteins have potential roles in epigenetic regulation throughmodification of 5mC to hmC.
