{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q6N021","secondaryAccessions":["B5MDU0","Q2TB88","Q3LIB8","Q96JX5","Q9HCM6","Q9NXW0"],"uniProtkbId":"TET2_HUMAN","entryAudit":{"firstPublicDate":"2008-03-18","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2009-06-16","entryVersion":166,"sequenceVersion":3},"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 TET2"},"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24315485"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32518946"}],"value":"1.14.11.80"}]}},"genes":[{"geneName":{"value":"TET2"},"synonyms":[{"value":"KIAA1546"}],"orfNames":[{"value":"Nbla00191"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19483684"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21057493"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21817016"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23222540"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23353889"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24315485"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32518946"}],"value":"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. Has a preference for 5-hydroxymethylcytosine in CpG motifs. 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, also 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"}],"commentType":"FUNCTION"},{"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":"24315485"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32518946"}]},"physiologicalReactions":[{"directionType":"left-to-right","reactionCrossReference":{"database":"Rhea","id":"RHEA:52637"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32518946"}]}]},{"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:0000269","source":"PubMed","id":"24315485"}]}},{"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:0000269","source":"PubMed","id":"24315485"}]}},{"commentType":"COFACTOR","cofactors":[{"name":"Fe(2+)","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24315485"}],"cofactorCrossReference":{"database":"ChEBI","id":"CHEBI:29033"}}],"note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24315485"}],"value":"Binds 1 Fe(2+) ion per subunit."}]}},{"commentType":"COFACTOR","cofactors":[{"name":"Zn(2+)","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24315485"}],"cofactorCrossReference":{"database":"ChEBI","id":"CHEBI:29105"}}],"note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24315485"}],"value":"Binds 3 zinc ions per subunit. The zinc ions have a structural role (PubMed:24315485)."}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23222540"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23353889"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24315485"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24357321"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25557551"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"34667079"}],"value":"Interacts with HCFC1 (PubMed:23353889). Interacts with OGT (PubMed:23222540, PubMed:23353889). Interacts with PROSER1; this interaction mediates TET2 O-GlcNAcylation and stability by promoting the interaction between OGT and TET2 (PubMed:34667079). Directly interacts (via C-terminus) with the DCAF1 component of the CRL4(VprBP) E3 ubiquitin-protein ligase complex (PubMed:24357321, PubMed:25557551)"}],"commentType":"SUBUNIT"},{"commentType":"INTERACTION","interactions":[{"interactantOne":{"uniProtKBAccession":"Q6N021","intActId":"EBI-310727"},"interactantTwo":{"uniProtKBAccession":"P22607","geneName":"FGFR3","intActId":"EBI-348399"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q6N021","intActId":"EBI-310727"},"interactantTwo":{"uniProtKBAccession":"P06396","geneName":"GSN","intActId":"EBI-351506"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q6N021","intActId":"EBI-310727"},"interactantTwo":{"uniProtKBAccession":"O15294","geneName":"OGT","intActId":"EBI-539828"},"numberOfExperiments":7,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q6N021","intActId":"EBI-310727"},"interactantTwo":{"uniProtKBAccession":"P29590","geneName":"PML","intActId":"EBI-295890"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q6N021","intActId":"EBI-310727"},"interactantTwo":{"uniProtKBAccession":"P04279","geneName":"SEMG1","intActId":"EBI-953955"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q6N021","intActId":"EBI-310727"},"interactantTwo":{"uniProtKBAccession":"P19544","geneName":"WT1","intActId":"EBI-2320534"},"numberOfExperiments":9,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q6N021-1","intActId":"EBI-20717492"},"interactantTwo":{"uniProtKBAccession":"O15294","geneName":"OGT","intActId":"EBI-539828"},"numberOfExperiments":5,"organismDiffer":false}]},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25557551"}],"value":"Localization to chromatin depends upon monoubiquitination at Lys-1299"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25557551"}],"value":"Nucleus","id":"SL-0191"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25557551"}],"value":"Chromosome","id":"SL-0468"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"1"},"isoformIds":["Q6N021-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"2"},"isoformIds":["Q6N021-2"],"sequenceIds":["VSP_032283","VSP_032284"],"isoformSequenceStatus":"Described"},{"name":{"value":"3"},"isoformIds":["Q6N021-3"],"sequenceIds":["VSP_032282","VSP_032285"],"isoformSequenceStatus":"Described"}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12646957"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19483684"}],"value":"Broadly expressed. Highly expressed in hematopoietic cells; highest expression observed in granulocytes. Expression is reduced in granulocytes from peripheral blood of patients affected by myelodysplastic syndromes"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23353889"}],"value":"May be glycosylated. It is unclear whether interaction with OGT leads to GlcNAcylation. According to a report, it is not GlcNAcylated by OGT (PubMed:23353889). In contrast, another group reports GlcNAcylation by OGT in mouse ortholog"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25557551"}],"value":"Monoubiquitinated at Lys-1299 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"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"39567688"}],"value":"Acetylated (PubMed:39567688). Deacetylase HDAC6 acts as a valine sensor by binding to valine through its primate-specific SE14 repeat region and deacetylates TET2 following valine deprivation which promotes TET2-dependent DNA demethylation (PubMed:39567688)"}],"commentType":"PTM"},{"commentType":"DISEASE","note":{"texts":[{"value":"TET2 is frequently mutated in myeloproliferative disorders (MPD). These constitute a heterogeneous group of disorders, also known as myeloproliferative diseases or myeloproliferative neoplasms (MPN), characterized by cellular proliferation of one or more hematologic cell lines in the peripheral blood, distinct from acute leukemia. Included diseases are: essential thrombocythemia, polycythemia vera, primary myelofibrosis (chronic idiopathic myelofibrosis). Bone marrow samples from patients display uniformly low levels of hmC in genomic DNA compared to bone marrow samples from healthy controls as well as hypomethylation relative to controls at the majority of differentially methylated CpG sites"}]}},{"commentType":"DISEASE","disease":{"diseaseId":"Polycythemia vera","diseaseAccession":"DI-02712","acronym":"PV","description":"A myeloproliferative disorder characterized by abnormal proliferation of all hematopoietic bone marrow elements, erythroid hyperplasia, an absolute increase in total blood volume, but also by myeloid leukocytosis, thrombocytosis and splenomegaly.","diseaseCrossReference":{"database":"MIM","id":"263300"}},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry"}]}},{"commentType":"DISEASE","note":{"texts":[{"value":"TET2 is frequently mutated in systemic mastocytosis; also known as systemic mast cell disease. A condition with features in common with myeloproliferative diseases. It is a clonal disorder of the mast cell and its precursor cells. The clinical symptoms and signs of systemic mastocytosis are due to accumulation of clonally derived mast cells in different tissues, including bone marrow, skin, the gastrointestinal tract, the liver, and the spleen"}]}},{"commentType":"DISEASE","disease":{"diseaseId":"Myelodysplastic syndrome","diseaseAccession":"DI-03291","acronym":"MDS","description":"A heterogeneous group of closely related clonal hematopoietic disorders. All are characterized by a hypercellular or hypocellular bone marrow with impaired morphology and maturation, dysplasia of the myeloid, megakaryocytic and/or erythroid lineages, and peripheral blood cytopenias resulting from ineffective blood cell production. Included diseases are: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS); chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative disease. MDS is considered a premalignant condition in a subgroup of patients that often progresses to acute myeloid leukemia (AML).","diseaseCrossReference":{"database":"MIM","id":"614286"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19372255"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19483684"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21057493"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry. Bone marrow samples from patients display uniformly low levels of hmC in genomic DNA compared to bone marrow samples from healthy controls as well as hypomethylation relative to controls at the majority of differentially methylated CpG sites"}]}},{"commentType":"DISEASE","disease":{"diseaseId":"Immunodeficiency 75 with lymphoproliferation","diseaseAccession":"DI-05992","acronym":"IMD75","description":"An autosomal recessive immunologic disorder characterized by recurrent infections, mainly viral and affecting the respiratory tract, immunodeficieny, immune dysregulation, and the development of lymphoproliferative disorders, including lymphoma.","diseaseCrossReference":{"database":"MIM","id":"619126"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32518946"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry"}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay"}],"commentType":"MISCELLANEOUS","molecule":"Isoform 3"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Belongs to the TET family"}],"commentType":"SIMILARITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"21817016"}],"value":"Subsequent steps in cytosine demethylation are subject to discussion. 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