{"results":[{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q8NFU7","secondaryAccessions":["A0A023HHK9","A0A023HHL0","Q5VUP7","Q7Z6B6","Q8TCR1","Q9C0I7"],"uniProtkbId":"TET1_HUMAN","entryAudit":{"firstPublicDate":"2006-10-03","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2006-10-03","entryVersion":171,"sequenceVersion":2},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"value":"Methylcytosine dioxygenase TET1"},"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19372391"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21496894"}],"value":"1.14.11.80"}]},"alternativeNames":[{"fullName":{"value":"CXXC-type zinc finger protein 6"}},{"fullName":{"value":"Leukemia-associated protein with a CXXC domain"}},{"fullName":{"value":"Ten-eleven translocation 1 gene protein"}}]},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"28397838"},{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:29484"}],"value":"TET1"},"synonyms":[{"value":"CXXC6"},{"value":"KIAA1676"},{"value":"LCX"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q3URK3"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12124344"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19372391"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19372393"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21496894"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21778364"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25284789"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29276034"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31278917"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33833093"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35798741"}],"value":"Dioxygenase that plays a key role in active DNA demethylation, by catalyzing the sequential oxidation of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) (PubMed:19372391, PubMed:21496894, PubMed:21778364, PubMed:35798741). In addition to its role in DNA demethylation, plays a more general role in chromatin regulation by recruiting histone modifying protein complexes to alter histone marks and chromatin accessibility, leading to both activation and repression of gene expression (PubMed:33833093). Plays therefore a role in many biological processes, including stem cell maintenance, T- and B-cell development, inflammation regulation, genomic imprinting, neural activity or DNA repair (PubMed:31278917). Involved in the balance between pluripotency and lineage commitment of cells and plays a role in embryonic stem cells maintenance and inner cell mass cell specification. Together with QSER1, plays an essential role in the protection and maintenance of transcriptional and developmental programs to inhibit the binding of DNMT3A/3B and therefore de novo methylation (PubMed:33833093). May play a role in pancreatic beta-cell specification during development. In this context, may function as an upstream epigenetic regulator of PAX4 presumably through direct recruitment by FOXA2 to a PAX4 enhancer to preserve its unmethylated status, thereby potentiating PAX4 expression to adopt beta-cell fate during endocrine lineage commitment (PubMed:35798741). Under DNA hypomethylation conditions, such as in female meiotic germ cells, may induce epigenetic reprogramming of pericentromeric heterochromatin (PCH), the constitutive heterochromatin of pericentromeric regions. PCH forms chromocenters in the interphase nucleus and chromocenters cluster at the prophase of meiosis. In this context, may also be essential for chromocenter clustering in a catalytic activity-independent manner, possibly through the recruitment polycomb repressive complex 1 (PRC1) to the chromocenters (By similarity). During embryonic development, may be required for normal meiotic progression in oocytes and meiotic gene activation (By similarity). Binds preferentially to DNA containing cytidine-phosphate-guanosine (CpG) dinucleotides over CpH (H=A, T, and C), hemimethylated-CpG and hemimethylated-hydroxymethyl-CpG (PubMed:29276034)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q3URK3"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28531272"}],"value":"Dioxygenase that plays a key role in active DNA demethylation (PubMed:28531272). Binds to promoters, particularly to those with high CG content (By similarity). In hippocampal neurons, isoform 1 regulates the expression of a unique subset of genes compared to isoform 2, although some overlap exists between both isoforms, hence differentially regulates excitatory synaptic transmission (By similarity). In hippocampal neuron cell cultures, isoform 1 controls both miniature excitatory postsynaptic current amplitude and frequency (By similarity). Isoform 1 may regulate genes involved in hippocampal-dependent memory, leading to positive regulation of memory, contrary to isoform 2 that may decrease memory (By similarity)"}],"commentType":"FUNCTION","molecule":"Isoform 1"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q3URK3"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28531272"}],"value":"Dioxygenase that plays a key role in active DNA demethylation (PubMed:28531272). As isoform 1, binds to promoters, particularly to those with high CG content, however displays reduced global chromatin affinity compared with isoform 1, leading to decreased global DNA demethylation compared with isoform 1 (By similarity). Contrary to isoform 1, isoform 2 localizes during S phase to sites of ongoing DNA replication in heterochromatin, causing a significant de novo 5hmC formation, globally, and more so in heterochromatin, including LINE 1 interspersed DNA repeats leading to their activation (By similarity). In hippocampal neurons, isoform 2 regulates the expression of a unique subset of genes compared to isoform 1, although some overlap between both isoforms, hence differentially regulates excitatory synaptic transmission (By similarity). In hippocampal neuron cell cultures, isoform 2 controls miniature excitatory postsynaptic current frequency, but not amplitude (By similarity). Isoform 2 may regulate genes involved in hippocampal-dependent memory, leading to negative regulation of memory, contrary to isoform 1 that may improve memory (By similarity). In immature and partially differentiated gonadotrope cells, directly represses luteinizing hormone gene LHB expression and does not catalyze 5hmC at the gene promoter (By similarity)"}],"commentType":"FUNCTION","molecule":"Isoform 2"},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"a 5-methyl-2'-deoxycytidine in DNA + 2-oxoglutarate + O2 = a 5-hydroxymethyl-2'-deoxycytidine in DNA + succinate + CO2","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:52636"},{"database":"Rhea","id":"RHEA-COMP:11370"},{"database":"Rhea","id":"RHEA-COMP:13315"},{"database":"ChEBI","id":"CHEBI:15379"},{"database":"ChEBI","id":"CHEBI:16526"},{"database":"ChEBI","id":"CHEBI:16810"},{"database":"ChEBI","id":"CHEBI:30031"},{"database":"ChEBI","id":"CHEBI:85454"},{"database":"ChEBI","id":"CHEBI:136731"}],"ecNumber":"1.14.11.80","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19372391"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21496894"}]}},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"a 5-hydroxymethyl-2'-deoxycytidine in DNA + 2-oxoglutarate + O2 = a 5-formyl-2'-deoxycytidine in DNA + succinate + CO2 + H2O","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:53828"},{"database":"Rhea","id":"RHEA-COMP:13315"},{"database":"Rhea","id":"RHEA-COMP:13656"},{"database":"ChEBI","id":"CHEBI:15377"},{"database":"ChEBI","id":"CHEBI:15379"},{"database":"ChEBI","id":"CHEBI:16526"},{"database":"ChEBI","id":"CHEBI:16810"},{"database":"ChEBI","id":"CHEBI:30031"},{"database":"ChEBI","id":"CHEBI:136731"},{"database":"ChEBI","id":"CHEBI:137731"}],"ecNumber":"1.14.11.80","evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"21778364"}]}},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"a 5-formyl-2'-deoxycytidine in DNA + 2-oxoglutarate + O2 = a 5-carboxyl-2'-deoxycytidine in DNA + succinate + CO2 + H(+)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:53832"},{"database":"Rhea","id":"RHEA-COMP:13656"},{"database":"Rhea","id":"RHEA-COMP:13657"},{"database":"ChEBI","id":"CHEBI:15378"},{"database":"ChEBI","id":"CHEBI:15379"},{"database":"ChEBI","id":"CHEBI:16526"},{"database":"ChEBI","id":"CHEBI:16810"},{"database":"ChEBI","id":"CHEBI:30031"},{"database":"ChEBI","id":"CHEBI:137731"},{"database":"ChEBI","id":"CHEBI:137732"}],"ecNumber":"1.14.11.80","evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"21778364"}]}},{"commentType":"COFACTOR","cofactors":[{"name":"Fe(2+)","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19372391"}],"cofactorCrossReference":{"database":"ChEBI","id":"CHEBI:29033"}}],"note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19372391"}],"value":"Binds 1 Fe(2+) ion per subunit."}]}},{"commentType":"COFACTOR","cofactors":[{"name":"Zn(2+)","evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q6N021"}],"cofactorCrossReference":{"database":"ChEBI","id":"CHEBI:29105"}}],"note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q6N021"}],"value":"Binds 3 zinc ions per subunit. The zinc ions have a structural role."}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q3URK3"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21490601"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24357321"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25557551"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33833093"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35798741"}],"value":"Interacts with SIN3A; recruits the transcriptional corepressor SIN3A to gene promoters (PubMed:21490601). Interacts with HCFC1 (By similarity). Interacts (via C-terminus) with OGT (By similarity). Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1 (By similarity). Interacts with QSER1 (PubMed:33833093). Interacts with NONO (via DNA-binding domain); this interaction recruits TET1 to genomic loci (By similarity). Interacts with FOXA2; this interaction may recruit TET1 to specific enhancers to preserve their unmethylated status and hence allowing gene expression (PubMed:35798741). Interacts with RNF2 (By similarity). Directly interacts (via C-terminus) with the DCAF1 component of the CRL4(VprBP) E3 ubiquitin-protein ligase complex (PubMed:24357321, PubMed:25557551)"}],"commentType":"SUBUNIT"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36056023"}],"value":"Interacts with UHRF1; this interaction induces the recruitment of TET1 to replicating heterochromatin (PubMed:36056023). Interacts with DCAF1 (PubMed:36056023)"}],"commentType":"SUBUNIT","molecule":"Isoform 2"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25557551"}],"value":"Localization to chromatin is promoted by monoubiquitination on Lys-1589"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q3URK3"}],"value":"Nucleus","id":"SL-0191"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33833093"}],"value":"Chromosome","id":"SL-0468"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Isoform 1","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q3URK3"}],"value":"Contrary to isoform 2, which accumulates at sites of ongoing DNA replication in heterochromatin, isoform 1 shows a homogeneous nuclear pattern during mitotic S phase"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36056023"}],"value":"Nucleus","id":"SL-0191"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q3URK3"}],"value":"Chromosome","id":"SL-0468"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Isoform 2","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36056023"}],"value":"During DNA replication, localizes to sites of ongoing DNA replication in heterochromatin (in late S phase) in an UHRF1- and CRL4(VprBP)-dependent manner, as a consequence of ubiquitination of the conserved residue Lys-1589. Localization to heterochromatin is independent of catalytic activity"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36056023"}],"value":"Nucleus","id":"SL-0191"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q3URK3"}],"value":"Chromosome","id":"SL-0468"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative promoter usage","Alternative splicing"],"isoforms":[{"name":{"value":"1"},"synonyms":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"28531272"}],"value":"TET1-FL"}],"isoformIds":["Q8NFU7-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"2"},"synonyms":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"36056023"}],"value":"TET1s"},{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"28531272"}],"value":"TET1-ALT"}],"isoformIds":["Q8NFU7-2"],"sequenceIds":["VSP_061826"],"isoformSequenceStatus":"Described"},{"name":{"value":"3"},"isoformIds":["Q8NFU7-3"],"sequenceIds":["VSP_061827"],"isoformSequenceStatus":"Described"},{"name":{"value":"4"},"isoformIds":["Q8NFU7-4"],"sequenceIds":["VSP_061828","VSP_061829"],"isoformSequenceStatus":"Described"}],"note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q3URK3"}],"value":"During development, a switch between isoforms 1 and 2 regulates DNA demethylation, imprint erasure and gene regulation. The switch may be controlled by alternative promoters."}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12124344"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12646957"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25284789"}],"value":"Expressed in fetal heart, lung and brain, and in adult skeletal muscle, thymus and ovary. Not detected in adult heart, lung or brain. Up-regulated in glioblastoma cells (at protein level) (PubMed:25284789)"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28531272"}],"value":"Expressed in embryonic stem cells (at protein level)"}],"commentType":"TISSUE SPECIFICITY","molecule":"Isoform 1"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q3URK3"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29276034"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36056023"}],"value":"The CXXC zinc finger plays a role in TET1 chromatin loading and participates in binding to CpG-DNA (PubMed:29276034). However, the global chromatin binding can be mediated by the entire N-terminus and occurs even in the absence of the CXXC domain (By similarity). The zinc finger domain impedes association DNA replication sites and prevents aberrant 5mC oxidation (PubMed:36056023)"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q3URK3"}],"value":"Glycosylated. Interaction with OGT leads to GlcNAcylation (By similarity)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25557551"}],"value":"Monoubiquitinated at Lys-1589 by the DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex called CRL4(VprBP) or CUL4A-RBX1-DDB1-DCAF1/VPRBP complex; this modification promotes binding to DNA"}],"commentType":"PTM"},{"commentType":"DISEASE","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12124344"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12646957"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25284789"}],"value":"A chromosomal aberration involving TET1 may be a cause of acute leukemias (PubMed:12646957). Translocation t(10;11)(q22;q23) with KMT2A/MLL1. This is a rare chromosomal translocation 5' KMT2A/MLL1-TET1 3' (PubMed:12124344, PubMed:12646957). Plays an important role in the tumorigenicity of glioblastoma cells. TET1-mediated production of 5hmC acts as a recruitment signal for the CHTOP-methylosome complex to selective sites on the chromosome, where it methylates H4R3 and activates the transcription of genes involved in glioblastoma genesis (PubMed:25284789)"}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"36056023"}],"value":"Produced by alternative promoter usage"}],"commentType":"MISCELLANEOUS","molecule":"Isoform 2"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305","source":"Reference","id":"Ref.2"}],"value":"Produced by alternative splicing"}],"commentType":"MISCELLANEOUS","molecule":"Isoform 3"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305","source":"Reference","id":"Ref.2"}],"value":"Produced by alternative splicing"}],"commentType":"MISCELLANEOUS","molecule":"Isoform 4"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Belongs to the TET family"}],"commentType":"SIMILARITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"21496894"}],"value":"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 (PubMed:21496894). 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"}],"commentType":"CAUTION"},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Miscellaneous discrepancy","sequence":"CAD28467.3","note":"Contaminating sequence. Potential poly-A sequence.","evidences":[{"evidenceCode":"ECO:0000305"}]}],"features":[{"type":"Chain","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":2136,"modifier":"EXACT"}},"description":"Methylcytosine dioxygenase TET1","featureId":"PRO_0000251949"},{"type":"Zinc finger","location":{"start":{"value":584,"modifier":"EXACT"},"end":{"value":625,"modifier":"EXACT"}},"description":"CXXC-type","evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00509"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29276034"}]},{"type":"Region","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":47,"modifier":"EXACT"}},"description":"Disordered","evidences":[{"evidenceCode":"ECO:0000256","source":"SAM","id":"MobiDB-lite"}]},{"type":"Region","location":{"start":{"value":528,"modifier":"EXACT"},"end":{"value":674,"modifier":"EXACT"}},"description":"Sufficient for binding to genomic CpG 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with DNA","evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q6N021"}]},{"type":"Region","location":{"start":{"value":1774,"modifier":"EXACT"},"end":{"value":1897,"modifier":"EXACT"}},"description":"Disordered","evidences":[{"evidenceCode":"ECO:0000256","source":"SAM","id":"MobiDB-lite"}]},{"type":"Region","location":{"start":{"value":1919,"modifier":"EXACT"},"end":{"value":1984,"modifier":"EXACT"}},"description":"Disordered","evidences":[{"evidenceCode":"ECO:0000256","source":"SAM","id":"MobiDB-lite"}]},{"type":"Region","location":{"start":{"value":2074,"modifier":"EXACT"},"end":{"value":2100,"modifier":"EXACT"}},"description":"Disordered","evidences":[{"evidenceCode":"ECO:0000256","source":"SAM","id":"MobiDB-lite"}]},{"type":"Compositional bias","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":12,"modifier":"EXACT"}},"description":"Basic residues","evidences":[{"evidenceCode":"ECO:0000256","source":"SAM","id":"MobiDB-lite"}]},{"type":"Compositional 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