{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q9Y6K1","secondaryAccessions":["E9PEB8","Q86TE8","Q86XF5","Q8IZV0","Q8WXU9"],"uniProtkbId":"DNM3A_HUMAN","entryAudit":{"firstPublicDate":"2001-09-26","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2008-01-15","entryVersion":213,"sequenceVersion":4},"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":"DNA (cytosine-5)-methyltransferase 3A"},"shortNames":[{"value":"Dnmt3a"}],"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12138111"}],"value":"2.1.1.37"}]},"alternativeNames":[{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Cysteine methyltransferase DNMT3A"},"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O88508"}],"value":"2.1.1.-"}]},{"fullName":{"value":"DNA methyltransferase HsaIIIA"},"shortNames":[{"value":"DNA MTase HsaIIIA"},{"value":"M.HsaIIIA"}]}]},"genes":[{"geneName":{"value":"DNMT3A"}}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O88508"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12138111"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"16357870"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30478443"}],"value":"Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development (PubMed:12138111, PubMed:16357870, PubMed:30478443). DNA methylation is coordinated with methylation of histones (PubMed:12138111, PubMed:16357870, PubMed:30478443). It modifies DNA in a non-processive manner and also methylates non-CpG sites (PubMed:12138111, PubMed:16357870, PubMed:30478443). May preferentially methylate DNA linker between 2 nucleosomal cores and is inhibited by histone H1 (By similarity). Plays a role in paternal and maternal imprinting (By similarity). Required for methylation of most imprinted loci in germ cells (By similarity). Acts as a transcriptional corepressor for ZBTB18 (By similarity). Recruited to trimethylated 'Lys-36' of histone H3 (H3K36me3) sites (By similarity). Can actively repress transcription through the recruitment of HDAC activity (By similarity). Also has weak auto-methylation activity on Cys-710 in absence of DNA (By similarity)"}],"commentType":"FUNCTION"},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"a 2'-deoxycytidine in DNA + S-adenosyl-L-methionine = a 5-methyl-2'-deoxycytidine in DNA + S-adenosyl-L-homocysteine + H(+)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:13681"},{"database":"Rhea","id":"RHEA-COMP:11369"},{"database":"Rhea","id":"RHEA-COMP:11370"},{"database":"ChEBI","id":"CHEBI:15378"},{"database":"ChEBI","id":"CHEBI:57856"},{"database":"ChEBI","id":"CHEBI:59789"},{"database":"ChEBI","id":"CHEBI:85452"},{"database":"ChEBI","id":"CHEBI:85454"}],"ecNumber":"2.1.1.37","evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU10018"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12138111"}]},"physiologicalReactions":[{"directionType":"left-to-right","reactionCrossReference":{"database":"Rhea","id":"RHEA:13682"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12138111"}]}]},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"L-cysteinyl-[protein] + S-adenosyl-L-methionine = S-methyl-L-cysteinyl-[protein] + S-adenosyl-L-homocysteine + H(+)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:66544"},{"database":"Rhea","id":"RHEA-COMP:10131"},{"database":"Rhea","id":"RHEA-COMP:10132"},{"database":"ChEBI","id":"CHEBI:15378"},{"database":"ChEBI","id":"CHEBI:29950"},{"database":"ChEBI","id":"CHEBI:57856"},{"database":"ChEBI","id":"CHEBI:59789"},{"database":"ChEBI","id":"CHEBI:82612"}],"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O88508"}]},"physiologicalReactions":[{"directionType":"left-to-right","reactionCrossReference":{"database":"Rhea","id":"RHEA:66545"},"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O88508"}]}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O88508"}],"value":"Activated by binding to the regulatory factor DNMT3L. Auto-methylation at Cys-710 in absence of DNA inactivates the DNA methyltransferase activity"}],"commentType":"ACTIVITY REGULATION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O88508"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12145218"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"16357870"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"16682412"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17713477"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19834512"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20871592"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"22086334"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32051553"}],"value":"Heterotetramer composed of 1 DNMT3A homodimer and 2 DNMT3L subunits (DNMT3L-DNMT3A-DNMT3A-DNMT3L) (PubMed:17713477, PubMed:19834512). Interacts with UBC9, PIAS1 and PIAS2 (By similarity). Binds the ZBTB18 transcriptional repressor (By similarity). Interacts with SETDB1 (PubMed:16682412). Associates with HDAC1 through its ADD domain (By similarity). Interacts with UHRF1 (By similarity). Interacts with DNMT1 and DNMT3B (PubMed:12145218). Interacts with the PRC2/EED-EZH2 complex (PubMed:16357870). Interacts with MPHOSPH8 (PubMed:20871592, PubMed:22086334). Interacts with histone H3 that is not methylated at 'Lys-4' (H3K4) (By similarity). Interacts with SPOCD1 (By similarity). Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression (PubMed:32051553)"}],"commentType":"SUBUNIT"},{"commentType":"INTERACTION","interactions":[{"interactantOne":{"uniProtKBAccession":"Q9Y6K1","intActId":"EBI-923653"},"interactantTwo":{"uniProtKBAccession":"Q03060","geneName":"CREM","intActId":"EBI-3907794"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q9Y6K1","intActId":"EBI-923653"},"interactantTwo":{"uniProtKBAccession":"Q9Y6K1","geneName":"DNMT3A","intActId":"EBI-923653"},"numberOfExperiments":4,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q9Y6K1","intActId":"EBI-923653"},"interactantTwo":{"uniProtKBAccession":"Q9UBC3","geneName":"DNMT3B","intActId":"EBI-80125"},"numberOfExperiments":4,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q9Y6K1","intActId":"EBI-923653"},"interactantTwo":{"uniProtKBAccession":"Q9UJW3-1","geneName":"DNMT3L","intActId":"EBI-15650345"},"numberOfExperiments":5,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q9Y6K1","intActId":"EBI-923653"},"interactantTwo":{"uniProtKBAccession":"O75530","geneName":"EED","intActId":"EBI-923794"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q9Y6K1","intActId":"EBI-923653"},"interactantTwo":{"uniProtKBAccession":"Q15910","geneName":"EZH2","intActId":"EBI-530054"},"numberOfExperiments":6,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q9Y6K1","intActId":"EBI-923653"},"interactantTwo":{"uniProtKBAccession":"P84243","geneName":"H3-3B","intActId":"EBI-120658"},"numberOfExperiments":7,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q9Y6K1","intActId":"EBI-923653"},"interactantTwo":{"uniProtKBAccession":"Q99750","geneName":"MDFI","intActId":"EBI-724076"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q9Y6K1","intActId":"EBI-923653"},"interactantTwo":{"uniProtKBAccession":"Q6FHY5","geneName":"MEOX2","intActId":"EBI-16439278"},"numberOfExperiments":4,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q9Y6K1","intActId":"EBI-923653"},"interactantTwo":{"uniProtKBAccession":"P32242","geneName":"OTX1","intActId":"EBI-740446"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q9Y6K1","intActId":"EBI-923653"},"interactantTwo":{"uniProtKBAccession":"O14744","geneName":"PRMT5","intActId":"EBI-351098"},"numberOfExperiments":4,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q9Y6K1","intActId":"EBI-923653"},"interactantTwo":{"uniProtKBAccession":"Q15047","geneName":"SETDB1","intActId":"EBI-79691"},"numberOfExperiments":7,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q9Y6K1","intActId":"EBI-923653"},"interactantTwo":{"uniProtKBAccession":"P23497","geneName":"SP100","intActId":"EBI-751145"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q9Y6K1","intActId":"EBI-923653"},"interactantTwo":{"uniProtKBAccession":"P56279","geneName":"TCL1A","intActId":"EBI-749995"},"numberOfExperiments":13,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q9Y6K1","intActId":"EBI-923653"},"interactantTwo":{"uniProtKBAccession":"Q96T88","geneName":"UHRF1","intActId":"EBI-1548946"},"numberOfExperiments":7,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q9Y6K1","intActId":"EBI-923653"},"interactantTwo":{"uniProtKBAccession":"O76024","geneName":"WFS1","intActId":"EBI-720609"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q9Y6K1","intActId":"EBI-923653"},"interactantTwo":{"uniProtKBAccession":"Q8N8E2","geneName":"ZNF513","intActId":"EBI-10279993"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q9Y6K1","intActId":"EBI-923653"},"interactantTwo":{"uniProtKBAccession":"Q9QR71","geneName":"LANA1","intActId":"EBI-15602554"},"numberOfExperiments":3,"organismDiffer":true}]},{"commentType":"SUBCELLULAR 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It specifically recognizes and binds trimethylated 'Lys-36' of histone H3 (H3K36me3) (By similarity)"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O88508"}],"value":"Sumoylated; sumoylation disrupts the ability to interact with histone deacetylases (HDAC1 and HDAC2) and repress transcription"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O88508"}],"value":"Auto-methylated at Cys-710: auto-methylation takes place in absence of DNA substrate and inactivates the DNA methyltransferase activity. Inactivation by auto-methylation may be used to inactivate unused DNA methyltransferases in the cell"}],"commentType":"PTM"},{"commentType":"DISEASE","disease":{"diseaseId":"Tatton-Brown-Rahman syndrome","diseaseAccession":"DI-04151","acronym":"TBRS","description":"An overgrowth syndrome characterized by a distinctive facial appearance, tall stature and intellectual disability. 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AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes.","diseaseCrossReference":{"database":"MIM","id":"601626"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21067377"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry"}]}},{"commentType":"DISEASE","disease":{"diseaseId":"Heyn-Sproul-Jackson syndrome","diseaseAccession":"DI-05727","acronym":"HESJAS","description":"An autosomal dominant form of microcephalic dwarfism. Affected individuals have intrauterine growth retardation, postnatal growth restrictions, proportionate short stature, microcephaly, severe developmental delay and impaired intellectual development. More variable features include sparse hair, short broad metacarpals and phalanges, and mild recurrent infections.","diseaseCrossReference":{"database":"MIM","id":"618724"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30478443"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry"}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"It is uncertain whether Met-1 or Met-35 is the initiator"}],"commentType":"MISCELLANEOUS","molecule":"Isoform 2"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Produced by alternative splicing"}],"commentType":"MISCELLANEOUS","molecule":"Isoform 3"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU01016"}],"value":"Belongs to the class I-like SAM-binding methyltransferase superfamily. 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