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Database: UniProt
Entry: Q9Y6K1
LinkDB: Q9Y6K1
Original site: Q9Y6K1 
ID   DNM3A_HUMAN             Reviewed;         912 AA.
AC   Q9Y6K1; E9PEB8; Q86TE8; Q86XF5; Q8IZV0; Q8WXU9;
DT   26-SEP-2001, integrated into UniProtKB/Swiss-Prot.
DT   15-JAN-2008, sequence version 4.
DT   23-FEB-2022, entry version 192.
DE   RecName: Full=DNA (cytosine-5)-methyltransferase 3A;
DE            Short=Dnmt3a;
DE            EC=2.1.1.37 {ECO:0000269|PubMed:12138111};
DE   AltName: Full=Cysteine methyltransferase DNMT3A {ECO:0000305};
DE            EC=2.1.1.- {ECO:0000250|UniProtKB:O88508};
DE   AltName: Full=DNA methyltransferase HsaIIIA;
DE            Short=DNA MTase HsaIIIA;
DE            Short=M.HsaIIIA;
GN   Name=DNMT3A;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC   TISSUE=Fetal testis;
RX   PubMed=10433969; DOI=10.1016/s0378-1119(99)00252-8;
RA   Xie S., Wang Z., Okano M., Nogami M., Li Y., He W.-W., Okumura K., Li E.;
RT   "Cloning, expression and chromosome locations of the human DNMT3 gene
RT   family.";
RL   Gene 236:87-95(1999).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=12138111; DOI=10.1074/jbc.m205312200;
RA   Chen T., Ueda Y., Xie S., Li E.;
RT   "A novel Dnmt3a isoform produced from an alternative promoter localizes to
RT   euchromatin and its expression correlates with active de novo
RT   methylation.";
RL   J. Biol. Chem. 277:38746-38754(2002).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH DNMT1 AND DNMT3B,
RP   AND SUBCELLULAR LOCATION.
RX   PubMed=12145218; DOI=10.1093/emboj/cdf401;
RA   Kim G.-D., Ni J., Kelesoglu N., Roberts R.J., Pradhan S.;
RT   "Co-operation and communication between the human maintenance and de novo
RT   DNA (cytosine-5) methyltransferases.";
RL   EMBO J. 21:4183-4195(2002).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15815621; DOI=10.1038/nature03466;
RA   Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA   Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA   Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA   Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA   Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA   Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA   Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA   Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA   Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA   McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA   Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA   Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA   Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA   Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA   Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA   Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA   Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA   Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA   Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA   Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA   Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA   Wilson R.K.;
RT   "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT   4.";
RL   Nature 434:724-731(2005).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
RC   TISSUE=Lung, PNS, and Skin;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [7]
RP   TISSUE SPECIFICITY.
RX   PubMed=10325416; DOI=10.1093/nar/27.11.2291;
RA   Robertson K.D., Uzvolgyi E., Liang G., Talmadge C., Sumegi J.,
RA   Gonzales F.A., Jones P.A.;
RT   "The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA
RT   expression in normal tissues and overexpression in tumors.";
RL   Nucleic Acids Res. 27:2291-2298(1999).
RN   [8]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-105, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA   Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT   "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT   networks.";
RL   Cell 127:635-648(2006).
RN   [9]
RP   INTERACTION WITH SETDB1.
RX   PubMed=16682412; DOI=10.1074/jbc.m513249200;
RA   Li H., Rauch T., Chen Z.-X., Szabo P.E., Riggs A.D., Pfeifer G.P.;
RT   "The histone methyltransferase SETDB1 and the DNA methyltransferase DNMT3A
RT   interact directly and localize to promoters silenced in cancer cells.";
RL   J. Biol. Chem. 281:19489-19500(2006).
RN   [10]
RP   FUNCTION, AND INTERACTION WITH THE PRC2/EED-EZH2 COMPLEX.
RX   PubMed=16357870; DOI=10.1038/nature04431;
RA   Vire E., Brenner C., Deplus R., Blanchon L., Fraga M., Didelot C.,
RA   Morey L., Van Eynde A., Bernard D., Vanderwinden J.-M., Bollen M.,
RA   Esteller M., Di Croce L., de Launoit Y., Fuks F.;
RT   "The Polycomb group protein EZH2 directly controls DNA methylation.";
RL   Nature 439:871-874(2006).
RN   [11]
RP   ERRATUM OF PUBMED:16357870.
RA   Vire E., Brenner C., Deplus R., Blanchon L., Fraga M., Didelot C.,
RA   Morey L., Van Eynde A., Bernard D., Vanderwinden J.-M., Bollen M.,
RA   Esteller M., Di Croce L., de Launoit Y., Fuks F.;
RL   Nature 446:824-824(2006).
RN   [12]
RP   DE NOVO DNA METHYLATION OF TARGET GENES.
RX   PubMed=17200670; DOI=10.1038/ng1950;
RA   Schlesinger Y., Straussman R., Keshet I., Farkash S., Hecht M.,
RA   Zimmerman J., Eden E., Yakhini Z., Ben-Shushan E., Reubinoff B.E.,
RA   Bergman Y., Simon I., Cedar H.;
RT   "Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for
RT   de novo methylation in cancer.";
RL   Nat. Genet. 39:232-236(2007).
RN   [13]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-105, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [14]
RP   INTERACTION WITH MPHOSPH8.
RX   PubMed=20871592; DOI=10.1038/emboj.2010.239;
RA   Kokura K., Sun L., Bedford M.T., Fang J.;
RT   "Methyl-H3K9-binding protein MPP8 mediates E-cadherin gene silencing and
RT   promotes tumour cell motility and invasion.";
RL   EMBO J. 29:3673-3687(2010).
RN   [15]
RP   INVOLVEMENT IN AML, AND VARIANTS AML HIS-882 AND CYS-882.
RX   PubMed=21067377; DOI=10.1056/nejmoa1005143;
RA   Ley T.J., Ding L., Walter M.J., McLellan M.D., Lamprecht T., Larson D.E.,
RA   Kandoth C., Payton J.E., Baty J., Welch J., Harris C.C., Lichti C.F.,
RA   Townsend R.R., Fulton R.S., Dooling D.J., Koboldt D.C., Schmidt H.,
RA   Zhang Q., Osborne J.R., Lin L., O'Laughlin M., McMichael J.F.,
RA   Delehaunty K.D., McGrath S.D., Fulton L.A., Magrini V.J., Vickery T.L.,
RA   Hundal J., Cook L.L., Conyers J.J., Swift G.W., Reed J.P., Alldredge P.A.,
RA   Wylie T., Walker J., Kalicki J., Watson M.A., Heath S., Shannon W.D.,
RA   Varghese N., Nagarajan R., Westervelt P., Tomasson M.H., Link D.C.,
RA   Graubert T.A., DiPersio J.F., Mardis E.R., Wilson R.K.;
RT   "DNMT3A mutations in acute myeloid leukemia.";
RL   N. Engl. J. Med. 363:2424-2433(2010).
RN   [16]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-243, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA   Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA   Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT   "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT   site occupancy during mitosis.";
RL   Sci. Signal. 3:RA3-RA3(2010).
RN   [17]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-105; SER-243; SER-255;
RP   THR-261 AND SER-267, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP   ANALYSIS].
RX   PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA   Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA   Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT   "System-wide temporal characterization of the proteome and phosphoproteome
RT   of human embryonic stem cell differentiation.";
RL   Sci. Signal. 4:RS3-RS3(2011).
RN   [18]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-105, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [19]
RP   INVOLVEMENT IN TBRS, AND VARIANTS TBRS ASN-310; SER-532; LYS-548; ARG-549;
RP   PRO-648; LEU-700; CYS-749; ASP-838; SER-902 AND LEU-904.
RX   PubMed=24614070; DOI=10.1038/ng.2917;
RG   Childhood Overgrowth Consortium;
RA   Tatton-Brown K., Seal S., Ruark E., Harmer J., Ramsay E.,
RA   Del Vecchio Duarte S., Zachariou A., Hanks S., O'Brien E., Aksglaede L.,
RA   Baralle D., Dabir T., Gener B., Goudie D., Homfray T., Kumar A., Pilz D.T.,
RA   Selicorni A., Temple I.K., Van Maldergem L., Yachelevich N.,
RA   van Montfort R., Rahman N.;
RT   "Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth
RT   syndrome with intellectual disability.";
RL   Nat. Genet. 46:385-388(2014).
RN   [20]
RP   SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-162, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=28112733; DOI=10.1038/nsmb.3366;
RA   Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C.,
RA   Nielsen M.L.;
RT   "Site-specific mapping of the human SUMO proteome reveals co-modification
RT   with phosphorylation.";
RL   Nat. Struct. Mol. Biol. 24:325-336(2017).
RN   [21]
RP   INVOLVEMENT IN HESJAS, VARIANTS HESJAS ARG-330 AND ASN-333,
RP   CHARACTERIZATION OF VARIANTS HESJAS ARG-330 AND ASN-333, AND FUNCTION.
RX   PubMed=30478443; DOI=10.1038/s41588-018-0274-x;
RA   Heyn P., Logan C.V., Fluteau A., Challis R.C., Auchynnikava T.,
RA   Martin C.A., Marsh J.A., Taglini F., Kilanowski F., Parry D.A.,
RA   Cormier-Daire V., Fong C.T., Gibson K., Hwa V., Ibanez L., Robertson S.P.,
RA   Sebastiani G., Rappsilber J., Allshire R.C., Reijns M.A.M., Dauber A.,
RA   Sproul D., Jackson A.P.;
RT   "Gain-of-function DNMT3A mutations cause microcephalic dwarfism and
RT   hypermethylation of Polycomb-regulated regions.";
RL   Nat. Genet. 51:96-105(2019).
RN   [22]
RP   INTERACTION WITH ZNF263.
RX   PubMed=32051553; DOI=10.1038/s41388-020-1206-7;
RA   Yu Z., Feng J., Wang W., Deng Z., Zhang Y., Xiao L., Wang Z., Liu C.,
RA   Liu Q., Chen S., Wu M.;
RT   "The EGFR-ZNF263 signaling axis silences SIX3 in glioblastoma
RT   epigenetically.";
RL   Oncogene 39:3163-3178(2020).
RN   [23]
RP   X-RAY CRYSTALLOGRAPHY (2.89 ANGSTROMS) OF 627-909 IN COMPLEX WITH
RP   S-ADENOSYL-L-HOMOCYSTEINE, SUBUNIT, AND MUTAGENESIS OF PHE-732.
RX   PubMed=17713477; DOI=10.1038/nature06146;
RA   Jia D., Jurkowska R.Z., Zhang X., Jeltsch A., Cheng X.;
RT   "Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA
RT   methylation.";
RL   Nature 449:248-251(2007).
RN   [24]
RP   X-RAY CRYSTALLOGRAPHY (2.29 ANGSTROMS) OF 476-614 IN COMPLEXES WITH ZINC
RP   AND WITH HISTONE H3 PEPTIDE, AND SUBUNIT.
RX   PubMed=19834512; DOI=10.1038/embor.2009.218;
RA   Otani J., Nankumo T., Arita K., Inamoto S., Ariyoshi M., Shirakawa M.;
RT   "Structural basis for recognition of H3K4 methylation status by the DNA
RT   methyltransferase 3A ATRX-DNMT3-DNMT3L domain.";
RL   EMBO Rep. 10:1235-1241(2009).
RN   [25]
RP   X-RAY CRYSTALLOGRAPHY (2.31 ANGSTROMS) OF 40-53 IN COMPLEX WITH MPHOSPH8,
RP   AND INTERACTION WITH MPHOSPH8.
RX   PubMed=22086334; DOI=10.1038/ncomms1549;
RA   Chang Y., Sun L., Kokura K., Horton J.R., Fukuda M., Espejo A., Izumi V.,
RA   Koomen J.M., Bedford M.T., Zhang X., Shinkai Y., Fang J., Cheng X.;
RT   "MPP8 mediates the interactions between DNA methyltransferase Dnmt3a and
RT   H3K9 methyltransferase GLP/G9a.";
RL   Nat. Commun. 2:533-533(2011).
RN   [26]
RP   X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 275-427.
RX   PubMed=21720545; DOI=10.1371/journal.pone.0018919;
RA   Wu H., Zeng H., Lam R., Tempel W., Amaya M.F., Xu C., Dombrovski L.,
RA   Qiu W., Wang Y., Min J.;
RT   "Structural and histone binding ability characterizations of human PWWP
RT   domains.";
RL   PLoS ONE 6:E18919-E18919(2011).
RN   [27]
RP   VARIANTS ASP-699; PHE-731 DEL; CYS-882; HIS-882 AND PRO-882.
RX   PubMed=21828135; DOI=10.1182/blood-2010-10-311019;
RA   Jankowska A.M., Makishima H., Tiu R.V., Szpurka H., Huang Y., Traina F.,
RA   Visconte V., Sugimoto Y., Prince C., O'Keefe C., Hsi E.D., List A.,
RA   Sekeres M.A., Rao A., McDevitt M.A., Maciejewski J.P.;
RT   "Mutational spectrum analysis of chronic myelomonocytic leukemia includes
RT   genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A.";
RL   Blood 118:3932-3941(2011).
RN   [28]
RP   VARIANT TBRS GLN-771.
RX   PubMed=27701732; DOI=10.1111/cge.12878;
RA   Xin B., Cruz Marino T., Szekely J., Leblanc J., Cechner K., Sency V.,
RA   Wensel C., Barabas M., Therriault V., Wang H.;
RT   "Novel DNMT3A germline mutations are associated with inherited Tatton-
RT   Brown-Rahman syndrome.";
RL   Clin. Genet. 91:623-628(2017).
RN   [29]
RP   VARIANTS TBRS CYS-365; ASN-529; GLY-778 AND CYS-882.
RX   PubMed=27317772; DOI=10.1136/jmedgenet-2015-103638;
RA   Tlemsani C., Luscan A., Leulliot N., Bieth E., Afenjar A., Baujat G.,
RA   Doco-Fenzy M., Goldenberg A., Lacombe D., Lambert L., Odent S., Pasche J.,
RA   Sigaudy S., Buffet A., Violle-Poirsier C., Briand-Suleau A., Laurendeau I.,
RA   Chin M., Saugier-Veber P., Vidaud D., Cormier-Daire V., Vidaud M.,
RA   Pasmant E., Burglen L.;
RT   "SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort.";
RL   J. Med. Genet. 53:743-751(2016).
RN   [30]
RP   VARIANT TBRS HIS-882.
RX   PubMed=27991732; DOI=10.1002/ajmg.a.37995;
RA   Kosaki R., Terashima H., Kubota M., Kosaki K.;
RT   "Acute myeloid leukemia-associated DNMT3A p.Arg882His mutation in a patient
RT   with Tatton-Brown-Rahman overgrowth syndrome as a constitutional
RT   mutation.";
RL   Am. J. Med. Genet. A 173:250-253(2017).
RN   [31]
RP   VARIANTS TBRS CYS-882 AND HIS-882.
RX   PubMed=28941052; DOI=10.1002/ajmg.a.38485;
RA   Shen W., Heeley J.M., Carlston C.M., Acuna-Hidalgo R., Nillesen W.M.,
RA   Dent K.M., Douglas G.V., Levine K.L., Bayrak-Toydemir P., Marcelis C.L.,
RA   Shinawi M., Carey J.C.;
RT   "The spectrum of DNMT3A variants in Tatton-Brown-Rahman syndrome overlaps
RT   with that in hematologic malignancies.";
RL   Am. J. Med. Genet. A 173:3022-3028(2017).
RN   [32]
RP   VARIANT TBRS CYS-882.
RX   PubMed=28432085; DOI=10.1136/jmedgenet-2017-104574;
RA   Hollink I.H.I.M., van den Ouweland A.M.W., Beverloo H.B.,
RA   Arentsen-Peters S.T.C.J.M., Zwaan C.M., Wagner A.;
RT   "Acute myeloid leukaemia in a case with Tatton-Brown-Rahman syndrome: the
RT   peculiar DNMT3A R882 mutation.";
RL   J. Med. Genet. 54:805-808(2017).
CC   -!- FUNCTION: Required for genome-wide de novo methylation and is essential
CC       for the establishment of DNA methylation patterns during development
CC       (PubMed:12138111, PubMed:16357870, PubMed:30478443). DNA methylation is
CC       coordinated with methylation of histones (PubMed:12138111,
CC       PubMed:16357870, PubMed:30478443). It modifies DNA in a non-processive
CC       manner and also methylates non-CpG sites (PubMed:12138111,
CC       PubMed:16357870, PubMed:30478443). May preferentially methylate DNA
CC       linker between 2 nucleosomal cores and is inhibited by histone H1 (By
CC       similarity). Plays a role in paternal and maternal imprinting (By
CC       similarity). Required for methylation of most imprinted loci in germ
CC       cells (By similarity). Acts as a transcriptional corepressor for ZBTB18
CC       (By similarity). Recruited to trimethylated 'Lys-36' of histone H3
CC       (H3K36me3) sites (By similarity). Can actively repress transcription
CC       through the recruitment of HDAC activity (By similarity). Also has weak
CC       auto-methylation activity on Cys-710 in absence of DNA (By similarity).
CC       {ECO:0000250|UniProtKB:O88508, ECO:0000269|PubMed:12138111,
CC       ECO:0000269|PubMed:16357870, ECO:0000269|PubMed:30478443}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a 2'-deoxycytidine in DNA + S-adenosyl-L-methionine = a 5-
CC         methyl-2'-deoxycytidine in DNA + H(+) + S-adenosyl-L-homocysteine;
CC         Xref=Rhea:RHEA:13681, Rhea:RHEA-COMP:11369, Rhea:RHEA-COMP:11370,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789,
CC         ChEBI:CHEBI:85452, ChEBI:CHEBI:85454; EC=2.1.1.37;
CC         Evidence={ECO:0000255|PROSITE-ProRule:PRU10018,
CC         ECO:0000269|PubMed:12138111};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:13682;
CC         Evidence={ECO:0000269|PubMed:12138111};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-cysteinyl-[protein] + S-adenosyl-L-methionine = H(+) + S-
CC         adenosyl-L-homocysteine + S-methyl-L-cysteinyl-[protein];
CC         Xref=Rhea:RHEA:66544, Rhea:RHEA-COMP:10131, Rhea:RHEA-COMP:10132,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:29950, ChEBI:CHEBI:57856,
CC         ChEBI:CHEBI:59789, ChEBI:CHEBI:82612;
CC         Evidence={ECO:0000250|UniProtKB:O88508};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66545;
CC         Evidence={ECO:0000250|UniProtKB:O88508};
CC   -!- ACTIVITY REGULATION: Activated by binding to the regulatory factor
CC       DNMT3L. Auto-methylation at Cys-710 in absence of DNA inactivates the
CC       DNA methyltransferase activity. {ECO:0000250|UniProtKB:O88508}.
CC   -!- SUBUNIT: Heterotetramer composed of 1 DNMT3A homodimer and 2 DNMT3L
CC       subunits (DNMT3L-DNMT3A-DNMT3A-DNMT3L) (PubMed:17713477,
CC       PubMed:19834512). Interacts with UBC9, PIAS1 and PIAS2 (By similarity).
CC       Binds the ZBTB18 transcriptional repressor (By similarity). Interacts
CC       with SETDB1 (PubMed:16682412). Associates with HDAC1 through its ADD
CC       domain (By similarity). Interacts with UHRF1 (By similarity). Interacts
CC       with DNMT1 and DNMT3B (PubMed:12145218). Interacts with the PRC2/EED-
CC       EZH2 complex (PubMed:16357870). Interacts with MPHOSPH8
CC       (PubMed:20871592, PubMed:22086334). Interacts with histone H3 that is
CC       not methylated at 'Lys-4' (H3K4) (By similarity). Interacts with SPOCD1
CC       (By similarity). Interacts with ZNF263; recruited to the SIX3 promoter
CC       along with other proteins involved in chromatin modification and
CC       transcriptional corepression where it contributes to transcriptional
CC       repression (PubMed:32051553). {ECO:0000250|UniProtKB:O88508,
CC       ECO:0000269|PubMed:12145218, ECO:0000269|PubMed:16357870,
CC       ECO:0000269|PubMed:16682412, ECO:0000269|PubMed:17713477,
CC       ECO:0000269|PubMed:19834512, ECO:0000269|PubMed:20871592,
CC       ECO:0000269|PubMed:22086334, ECO:0000269|PubMed:32051553}.
CC   -!- INTERACTION:
CC       Q9Y6K1; Q03060: CREM; NbExp=2; IntAct=EBI-923653, EBI-3907794;
CC       Q9Y6K1; Q9Y6K1: DNMT3A; NbExp=4; IntAct=EBI-923653, EBI-923653;
CC       Q9Y6K1; Q9UBC3: DNMT3B; NbExp=3; IntAct=EBI-923653, EBI-80125;
CC       Q9Y6K1; Q9UJW3-1: DNMT3L; NbExp=5; IntAct=EBI-923653, EBI-15650345;
CC       Q9Y6K1; O75530: EED; NbExp=2; IntAct=EBI-923653, EBI-923794;
CC       Q9Y6K1; Q15910: EZH2; NbExp=6; IntAct=EBI-923653, EBI-530054;
CC       Q9Y6K1; P84243: H3-3B; NbExp=7; IntAct=EBI-923653, EBI-120658;
CC       Q9Y6K1; Q99750: MDFI; NbExp=3; IntAct=EBI-923653, EBI-724076;
CC       Q9Y6K1; Q6FHY5: MEOX2; NbExp=4; IntAct=EBI-923653, EBI-16439278;
CC       Q9Y6K1; P32242: OTX1; NbExp=3; IntAct=EBI-923653, EBI-740446;
CC       Q9Y6K1; O14744: PRMT5; NbExp=4; IntAct=EBI-923653, EBI-351098;
CC       Q9Y6K1; Q15047: SETDB1; NbExp=7; IntAct=EBI-923653, EBI-79691;
CC       Q9Y6K1; P23497: SP100; NbExp=3; IntAct=EBI-923653, EBI-751145;
CC       Q9Y6K1; P56279: TCL1A; NbExp=10; IntAct=EBI-923653, EBI-749995;
CC       Q9Y6K1; Q96T88: UHRF1; NbExp=7; IntAct=EBI-923653, EBI-1548946;
CC       Q9Y6K1; O76024: WFS1; NbExp=3; IntAct=EBI-923653, EBI-720609;
CC       Q9Y6K1; Q8N8E2: ZNF513; NbExp=3; IntAct=EBI-923653, EBI-10279993;
CC       Q9Y6K1; Q9QR71: LANA1; Xeno; NbExp=3; IntAct=EBI-923653, EBI-15602554;
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:12138111,
CC       ECO:0000269|PubMed:12145218}. Chromosome {ECO:0000269|PubMed:12138111}.
CC       Cytoplasm {ECO:0000269|PubMed:12145218}. Note=Accumulates in the major
CC       satellite repeats at pericentric heterochromatin.
CC       {ECO:0000250|UniProtKB:O88508}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative promoter usage, Alternative splicing; Named isoforms=3;
CC       Name=1;
CC         IsoId=Q9Y6K1-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q9Y6K1-2; Sequence=VSP_046254;
CC       Name=3;
CC         IsoId=Q9Y6K1-3; Sequence=VSP_040998, VSP_040999;
CC   -!- TISSUE SPECIFICITY: Highly expressed in fetal tissues, skeletal muscle,
CC       heart, peripheral blood mononuclear cells, kidney, and at lower levels
CC       in placenta, brain, liver, colon, spleen, small intestine and lung.
CC       {ECO:0000269|PubMed:10325416}.
CC   -!- DOMAIN: The PWWP domain is essential for targeting to pericentric
CC       heterochromatin. It specifically recognizes and binds trimethylated
CC       'Lys-36' of histone H3 (H3K36me3) (By similarity).
CC       {ECO:0000250|UniProtKB:O88508}.
CC   -!- PTM: Sumoylated; sumoylation disrupts the ability to interact with
CC       histone deacetylases (HDAC1 and HDAC2) and repress transcription.
CC       {ECO:0000250|UniProtKB:O88508}.
CC   -!- PTM: Auto-methylated at Cys-710: auto-methylation takes place in
CC       absence of DNA substrate and inactivates the DNA methyltransferase
CC       activity. Inactivation by auto-methylation may be used to inactivate
CC       unused DNA methyltransferases in the cell.
CC       {ECO:0000250|UniProtKB:O88508}.
CC   -!- DISEASE: Tatton-Brown-Rahman syndrome (TBRS) [MIM:615879]: An
CC       overgrowth syndrome characterized by a distinctive facial appearance,
CC       tall stature and intellectual disability. Facial gestalt is
CC       characterized by a round face, heavy horizontal eyebrows and narrow
CC       palpebral fissures. Less common features include atrial septal defects,
CC       seizures, umbilical hernia, and scoliosis.
CC       {ECO:0000269|PubMed:24614070, ECO:0000269|PubMed:27317772,
CC       ECO:0000269|PubMed:27701732, ECO:0000269|PubMed:27991732,
CC       ECO:0000269|PubMed:28432085, ECO:0000269|PubMed:28941052}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- DISEASE: Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of
CC       acute leukemia, a cancer of the white blood cells. AML is a malignant
CC       disease of bone marrow characterized by maturational arrest of
CC       hematopoietic precursors at an early stage of development. Clonal
CC       expansion of myeloid blasts occurs in bone marrow, blood, and other
CC       tissue. Myelogenous leukemias develop from changes in cells that
CC       normally produce neutrophils, basophils, eosinophils and monocytes.
CC       {ECO:0000269|PubMed:21067377}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- DISEASE: Heyn-Sproul-Jackson syndrome (HESJAS) [MIM:618724]: An
CC       autosomal dominant form of microcephalic dwarfism. Affected individuals
CC       have intrauterine growth retardation, postnatal growth restrictions,
CC       proportionate short stature, microcephaly, severe developmental delay
CC       and impaired intellectual development. More variable features include
CC       sparse hair, short broad metacarpals and phalanges, and mild recurrent
CC       infections. {ECO:0000269|PubMed:30478443}. Note=The disease is caused
CC       by variants affecting the gene represented in this entry.
CC   -!- MISCELLANEOUS: [Isoform 2]: It is uncertain whether Met-1 or Met-35 is
CC       the initiator. {ECO:0000305}.
CC   -!- MISCELLANEOUS: [Isoform 3]: Produced by alternative splicing.
CC       {ECO:0000305}.
CC   -!- SIMILARITY: Belongs to the class I-like SAM-binding methyltransferase
CC       superfamily. C5-methyltransferase family. {ECO:0000255|PROSITE-
CC       ProRule:PRU01016}.
CC   -!- CAUTION: It is uncertain whether Met-1 or Met-4 is the initiator.
CC       {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAL57039.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC       Sequence=AAN40037.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; AF067972; AAD33084.2; -; mRNA.
DR   EMBL; AF480163; AAN40037.1; ALT_INIT; mRNA.
DR   EMBL; AF331856; AAL57039.1; ALT_INIT; mRNA.
DR   EMBL; AC012074; AAY14761.1; -; Genomic_DNA.
DR   EMBL; CH471053; EAX00727.1; -; Genomic_DNA.
DR   EMBL; BC032392; AAH32392.1; -; mRNA.
DR   EMBL; BC043617; AAH43617.1; -; mRNA.
DR   EMBL; BC051864; AAH51864.1; -; mRNA.
DR   CCDS; CCDS1718.2; -. [Q9Y6K1-2]
DR   CCDS; CCDS33157.1; -. [Q9Y6K1-1]
DR   CCDS; CCDS46232.1; -. [Q9Y6K1-3]
DR   RefSeq; NP_001307821.1; NM_001320892.1. [Q9Y6K1-3]
DR   RefSeq; NP_001307822.1; NM_001320893.1.
DR   RefSeq; NP_072046.2; NM_022552.4. [Q9Y6K1-1]
DR   RefSeq; NP_715640.2; NM_153759.3. [Q9Y6K1-2]
DR   RefSeq; NP_783328.1; NM_175629.2. [Q9Y6K1-1]
DR   RefSeq; NP_783329.1; NM_175630.1. [Q9Y6K1-3]
DR   RefSeq; XP_005264232.1; XM_005264175.4. [Q9Y6K1-1]
DR   RefSeq; XP_005264234.1; XM_005264177.4.
DR   RefSeq; XP_011530969.1; XM_011532667.2.
DR   RefSeq; XP_016859015.1; XM_017003526.1. [Q9Y6K1-1]
DR   RefSeq; XP_016859016.1; XM_017003527.1.
DR   PDB; 2QRV; X-ray; 2.89 A; A/D/E/H=627-912.
DR   PDB; 3A1A; X-ray; 2.30 A; A=476-614.
DR   PDB; 3A1B; X-ray; 2.29 A; A=476-614.
DR   PDB; 3LLR; X-ray; 2.30 A; A/B/C/D/E=275-427.
DR   PDB; 3SVM; X-ray; 2.31 A; P=40-53.
DR   PDB; 4QBQ; X-ray; 2.41 A; A/C=479-610.
DR   PDB; 4QBR; X-ray; 1.90 A; A/C=476-611.
DR   PDB; 4QBS; X-ray; 1.80 A; A=476-611.
DR   PDB; 4U7P; X-ray; 3.82 A; A=455-912.
DR   PDB; 4U7T; X-ray; 2.90 A; A/C=476-912.
DR   PDB; 5YX2; X-ray; 2.65 A; A/D=628-912.
DR   PDB; 6BRR; X-ray; 2.97 A; A/D=628-912.
DR   PDB; 6F57; X-ray; 3.10 A; A/D=628-912.
DR   PDB; 6PA7; EM; 2.94 A; K/P=224-912.
DR   PDB; 6W89; X-ray; 2.50 A; A/D/G/J=628-912.
DR   PDB; 6W8B; X-ray; 2.40 A; A/D/H/K=628-912.
DR   PDB; 6W8D; X-ray; 2.60 A; A/D=628-912.
DR   PDB; 6W8J; X-ray; 2.44 A; A/D=628-912.
DR   PDBsum; 2QRV; -.
DR   PDBsum; 3A1A; -.
DR   PDBsum; 3A1B; -.
DR   PDBsum; 3LLR; -.
DR   PDBsum; 3SVM; -.
DR   PDBsum; 4QBQ; -.
DR   PDBsum; 4QBR; -.
DR   PDBsum; 4QBS; -.
DR   PDBsum; 4U7P; -.
DR   PDBsum; 4U7T; -.
DR   PDBsum; 5YX2; -.
DR   PDBsum; 6BRR; -.
DR   PDBsum; 6F57; -.
DR   PDBsum; 6PA7; -.
DR   PDBsum; 6W89; -.
DR   PDBsum; 6W8B; -.
DR   PDBsum; 6W8D; -.
DR   PDBsum; 6W8J; -.
DR   SMR; Q9Y6K1; -.
DR   BioGRID; 108125; 74.
DR   ComplexPortal; CPX-944; DNA (cytosine-5)-methyltransferase 3A complex.
DR   CORUM; Q9Y6K1; -.
DR   DIP; DIP-38004N; -.
DR   IntAct; Q9Y6K1; 41.
DR   MINT; Q9Y6K1; -.
DR   STRING; 9606.ENSP00000264709; -.
DR   BindingDB; Q9Y6K1; -.
DR   ChEMBL; CHEMBL1992; -.
DR   DrugBank; DB01262; Decitabine.
DR   DrugBank; DB00721; Procaine.
DR   DrugCentral; Q9Y6K1; -.
DR   REBASE; 4119; M.HsaDnmt3A.
DR   iPTMnet; Q9Y6K1; -.
DR   PhosphoSitePlus; Q9Y6K1; -.
DR   BioMuta; DNMT3A; -.
DR   DMDM; 166215081; -.
DR   EPD; Q9Y6K1; -.
DR   jPOST; Q9Y6K1; -.
DR   MassIVE; Q9Y6K1; -.
DR   MaxQB; Q9Y6K1; -.
DR   PaxDb; Q9Y6K1; -.
DR   PeptideAtlas; Q9Y6K1; -.
DR   PRIDE; Q9Y6K1; -.
DR   ProteomicsDB; 19854; -.
DR   ProteomicsDB; 86709; -. [Q9Y6K1-1]
DR   ProteomicsDB; 86710; -. [Q9Y6K1-2]
DR   ProteomicsDB; 86711; -. [Q9Y6K1-3]
DR   ABCD; Q9Y6K1; 1 sequenced antibody.
DR   Antibodypedia; 4006; 994 antibodies from 46 providers.
DR   DNASU; 1788; -.
DR   Ensembl; ENST00000264709; ENSP00000264709; ENSG00000119772.
DR   Ensembl; ENST00000321117; ENSP00000324375; ENSG00000119772.
DR   Ensembl; ENST00000380746; ENSP00000370122; ENSG00000119772. [Q9Y6K1-2]
DR   Ensembl; ENST00000406659; ENSP00000384852; ENSG00000119772. [Q9Y6K1-3]
DR   GeneID; 1788; -.
DR   KEGG; hsa:1788; -.
DR   MANE-Select; ENST00000321117.10; ENSP00000324375.5; NM_022552.5; NP_072046.2.
DR   UCSC; uc002rgb.5; human. [Q9Y6K1-1]
DR   CTD; 1788; -.
DR   DisGeNET; 1788; -.
DR   GeneCards; DNMT3A; -.
DR   HGNC; HGNC:2978; DNMT3A.
DR   HPA; ENSG00000119772; Low tissue specificity.
DR   MalaCards; DNMT3A; -.
DR   MIM; 601626; phenotype.
DR   MIM; 602769; gene.
DR   MIM; 615879; phenotype.
DR   MIM; 618724; phenotype.
DR   neXtProt; NX_Q9Y6K1; -.
DR   OpenTargets; ENSG00000119772; -.
DR   Orphanet; 276621; Sporadic pheochromocytoma/secreting paraganglioma.
DR   Orphanet; 404443; Tatton-Brown-Rahman syndrome.
DR   PharmGKB; PA27445; -.
DR   VEuPathDB; HostDB:ENSG00000119772; -.
DR   eggNOG; ENOG502QR6U; Eukaryota.
DR   GeneTree; ENSGT00940000155459; -.
DR   HOGENOM; CLU_121732_0_0_1; -.
DR   InParanoid; Q9Y6K1; -.
DR   OMA; DGKFSVX; -.
DR   OrthoDB; 1015783at2759; -.
DR   PhylomeDB; Q9Y6K1; -.
DR   TreeFam; TF329039; -.
DR   BRENDA; 2.1.1.37; 2681.
DR   PathwayCommons; Q9Y6K1; -.
DR   Reactome; R-HSA-212300; PRC2 methylates histones and DNA.
DR   Reactome; R-HSA-3214858; RMTs methylate histone arginines.
DR   Reactome; R-HSA-4655427; SUMOylation of DNA methylation proteins.
DR   Reactome; R-HSA-5334118; DNA methylation.
DR   Reactome; R-HSA-9710421; Defective pyroptosis.
DR   SignaLink; Q9Y6K1; -.
DR   SIGNOR; Q9Y6K1; -.
DR   BioGRID-ORCS; 1788; 7 hits in 1052 CRISPR screens.
DR   ChiTaRS; DNMT3A; human.
DR   EvolutionaryTrace; Q9Y6K1; -.
DR   GenomeRNAi; 1788; -.
DR   Pharos; Q9Y6K1; Tclin.
DR   PRO; PR:Q9Y6K1; -.
DR   Proteomes; UP000005640; Chromosome 2.
DR   RNAct; Q9Y6K1; protein.
DR   Bgee; ENSG00000119772; Expressed in female gonad and 191 other tissues.
DR   ExpressionAtlas; Q9Y6K1; baseline and differential.
DR   Genevisible; Q9Y6K1; HS.
DR   GO; GO:1902494; C:catalytic complex; IPI:ComplexPortal.
DR   GO; GO:0000775; C:chromosome, centromeric region; IEA:Ensembl.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0000791; C:euchromatin; IDA:UniProtKB.
DR   GO; GO:0000792; C:heterochromatin; IEA:Ensembl.
DR   GO; GO:0016363; C:nuclear matrix; IDA:UniProtKB.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0001741; C:XY body; IEA:Ensembl.
DR   GO; GO:0003682; F:chromatin binding; IEA:Ensembl.
DR   GO; GO:0003886; F:DNA (cytosine-5-)-methyltransferase activity; IDA:UniProtKB.
DR   GO; GO:0003677; F:DNA binding; IDA:UniProtKB.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0106363; F:protein-cysteine methyltransferase activity; ISS:UniProtKB.
DR   GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:BHF-UCL.
DR   GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:BHF-UCL.
DR   GO; GO:0003714; F:transcription corepressor activity; TAS:ARUK-UCL.
DR   GO; GO:0007568; P:aging; IEA:Ensembl.
DR   GO; GO:0090116; P:C-5 methylation of cytosine; IDA:ComplexPortal.
DR   GO; GO:0071230; P:cellular response to amino acid stimulus; IEA:Ensembl.
DR   GO; GO:1903926; P:cellular response to bisphenol A; IEA:Ensembl.
DR   GO; GO:0071361; P:cellular response to ethanol; IEA:Ensembl.
DR   GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl.
DR   GO; GO:0006306; P:DNA methylation; IDA:UniProtKB.
DR   GO; GO:0043045; P:DNA methylation involved in embryo development; IEA:Ensembl.
DR   GO; GO:0043046; P:DNA methylation involved in gamete generation; IEA:Ensembl.
DR   GO; GO:0006346; P:DNA methylation-dependent heterochromatin assembly; IEA:Ensembl.
DR   GO; GO:0097284; P:hepatocyte apoptotic process; IEA:Ensembl.
DR   GO; GO:0000278; P:mitotic cell cycle; IEA:Ensembl.
DR   GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:BHF-UCL.
DR   GO; GO:0030182; P:neuron differentiation; IEA:Ensembl.
DR   GO; GO:0010942; P:positive regulation of cell death; IEA:Ensembl.
DR   GO; GO:0006349; P:regulation of gene expression by genetic imprinting; TAS:UniProtKB.
DR   GO; GO:0042220; P:response to cocaine; IEA:Ensembl.
DR   GO; GO:0032355; P:response to estradiol; IEA:Ensembl.
DR   GO; GO:0010212; P:response to ionizing radiation; IEA:Ensembl.
DR   GO; GO:0010288; P:response to lead ion; IEA:Ensembl.
DR   GO; GO:0009636; P:response to toxic substance; IEA:Ensembl.
DR   GO; GO:0033189; P:response to vitamin A; IEA:Ensembl.
DR   GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR   GO; GO:0007283; P:spermatogenesis; IEA:Ensembl.
DR   CDD; cd11729; ADDz_Dnmt3a; 1.
DR   IDEAL; IID00336; -.
DR   InterPro; IPR025766; ADD.
DR   InterPro; IPR044108; ADD_DNMT3A.
DR   InterPro; IPR018117; C5_DNA_meth_AS.
DR   InterPro; IPR001525; C5_MeTfrase.
DR   InterPro; IPR040552; DNMT3_ADD.
DR   InterPro; IPR030487; DNMT3A.
DR   InterPro; IPR000313; PWWP_dom.
DR   InterPro; IPR029063; SAM-dependent_MTases.
DR   PANTHER; PTHR23068:SF10; PTHR23068:SF10; 1.
DR   Pfam; PF17980; ADD_DNMT3; 1.
DR   Pfam; PF00145; DNA_methylase; 1.
DR   Pfam; PF00855; PWWP; 1.
DR   SMART; SM00293; PWWP; 1.
DR   SUPFAM; SSF53335; SSF53335; 1.
DR   PROSITE; PS51533; ADD; 1.
DR   PROSITE; PS00094; C5_MTASE_1; 1.
DR   PROSITE; PS50812; PWWP; 1.
DR   PROSITE; PS51679; SAM_MT_C5; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative promoter usage; Alternative splicing;
KW   Chromatin regulator; Chromosome; Cytoplasm; Disease variant; DNA-binding;
KW   Dwarfism; Isopeptide bond; Mental retardation; Metal-binding; Methylation;
KW   Methyltransferase; Nucleus; Phosphoprotein; Reference proteome; Repressor;
KW   S-adenosyl-L-methionine; Transferase; Ubl conjugation; Zinc; Zinc-finger.
FT   CHAIN           1..912
FT                   /note="DNA (cytosine-5)-methyltransferase 3A"
FT                   /id="PRO_0000088043"
FT   DOMAIN          292..350
FT                   /note="PWWP"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00162"
FT   DOMAIN          482..614
FT                   /note="ADD"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00865"
FT   DOMAIN          634..912
FT                   /note="SAM-dependent MTase C5-type"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01016"
FT   ZN_FING         493..523
FT                   /note="GATA-type; atypical"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00865"
FT   ZN_FING         534..590
FT                   /note="PHD-type; atypical"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00865"
FT   REGION          1..178
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          199..403
FT                   /note="Interaction with DNMT1 and DNMT3B"
FT                   /evidence="ECO:0000269|PubMed:12145218"
FT   REGION          221..286
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          447..466
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          494..586
FT                   /note="Interaction with the PRC2/EED-EZH2 complex"
FT                   /evidence="ECO:0000250|UniProtKB:O88508"
FT   REGION          641..645
FT                   /note="S-adenosyl-L-methionine binding"
FT                   /evidence="ECO:0000269|PubMed:17713477,
FT                   ECO:0007744|PDB:2QRV"
FT   REGION          686..688
FT                   /note="S-adenosyl-L-methionine binding"
FT                   /evidence="ECO:0000269|PubMed:17713477,
FT                   ECO:0007744|PDB:2QRV"
FT   REGION          891..893
FT                   /note="S-adenosyl-L-methionine binding"
FT                   /evidence="ECO:0000269|PubMed:17713477,
FT                   ECO:0007744|PDB:2QRV"
FT   COMPBIAS        15..44
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        145..166
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        710
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01016,
FT                   ECO:0000255|PROSITE-ProRule:PRU10018"
FT   BINDING         664
FT                   /note="S-adenosyl-L-methionine"
FT                   /evidence="ECO:0000269|PubMed:17713477,
FT                   ECO:0007744|PDB:2QRV"
FT   MOD_RES         105
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:17081983,
FT                   ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:21406692,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         124
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:Q1LZ53"
FT   MOD_RES         171
FT                   /note="Omega-N-methylarginine"
FT                   /evidence="ECO:0000250|UniProtKB:O88508"
FT   MOD_RES         243
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:20068231,
FT                   ECO:0007744|PubMed:21406692"
FT   MOD_RES         255
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:21406692"
FT   MOD_RES         261
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:21406692"
FT   MOD_RES         267
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:21406692"
FT   MOD_RES         390
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O88508"
FT   MOD_RES         393
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O88508"
FT   MOD_RES         710
FT                   /note="S-methylcysteine; by autocatalysis"
FT                   /evidence="ECO:0000250|UniProtKB:O88508"
FT   CROSSLNK        162
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO2)"
FT                   /evidence="ECO:0007744|PubMed:28112733"
FT   VAR_SEQ         1..213
FT                   /note="MPAMPSSGPGDTSSSAAEREEDRKDGEEQEEPRGKEERQEPSTTARKVGRPG
FT                   RKRKHPPVESGDTPKDPAVISKSPSMAQDSGASELLPNGDLEKRSEPQPEEGSPAGGQK
FT                   GGAPAEGEGAAETLPEASRAVENGCCTPKEGRGAPAEAGKEQKETNIESMKMEGSRGRL
FT                   RGGLGWESSLRQRPMPRLTFQAGDPYYISKRKRDEWLARWKRE -> MGILERVVRRNG
FT                   RVDRSLKDECDT (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:12138111"
FT                   /id="VSP_046254"
FT   VAR_SEQ         151..166
FT                   /note="KEQKETNIESMKMEGS -> ESSAPGAASSGPTSIP (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_040998"
FT   VAR_SEQ         167..912
FT                   /note="Missing (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_040999"
FT   VARIANT         310
FT                   /note="I -> N (in TBRS; somatic mutation;
FT                   dbSNP:rs587777508)"
FT                   /evidence="ECO:0000269|PubMed:24614070"
FT                   /id="VAR_071463"
FT   VARIANT         330
FT                   /note="W -> R (in HESJAS; no effect on protein expression;
FT                   changed DNA methylation; results in aberrant expression of
FT                   genes involved in developmental processes)"
FT                   /evidence="ECO:0000269|PubMed:30478443"
FT                   /id="VAR_083539"
FT   VARIANT         333
FT                   /note="D -> N (in HESJAS; changed DNA methylation; results
FT                   in aberrant expression of genes involved in developmental
FT                   processes)"
FT                   /evidence="ECO:0000269|PubMed:30478443"
FT                   /id="VAR_083540"
FT   VARIANT         365
FT                   /note="Y -> C (in TBRS; unknown pathological significance;
FT                   dbSNP:rs144062658)"
FT                   /evidence="ECO:0000269|PubMed:27317772"
FT                   /id="VAR_077522"
FT   VARIANT         529
FT                   /note="D -> N (in TBRS; unknown pathological significance;
FT                   dbSNP:rs962805778)"
FT                   /evidence="ECO:0000269|PubMed:27317772"
FT                   /id="VAR_077523"
FT   VARIANT         532
FT                   /note="G -> S (in TBRS; somatic mutation;
FT                   dbSNP:rs951361433)"
FT                   /evidence="ECO:0000269|PubMed:24614070"
FT                   /id="VAR_071464"
FT   VARIANT         548
FT                   /note="M -> K (in TBRS; somatic mutation;
FT                   dbSNP:rs587777509)"
FT                   /evidence="ECO:0000269|PubMed:24614070"
FT                   /id="VAR_071465"
FT   VARIANT         549
FT                   /note="C -> R (in TBRS; somatic mutation)"
FT                   /evidence="ECO:0000269|PubMed:24614070"
FT                   /id="VAR_071466"
FT   VARIANT         648
FT                   /note="L -> P (in TBRS; somatic mutation;
FT                   dbSNP:rs587777507)"
FT                   /evidence="ECO:0000269|PubMed:24614070"
FT                   /id="VAR_071467"
FT   VARIANT         699
FT                   /note="G -> D (in a patient with chronic myelomonocytic
FT                   leukemia; dbSNP:rs761064473)"
FT                   /evidence="ECO:0000269|PubMed:21828135"
FT                   /id="VAR_067234"
FT   VARIANT         700
FT                   /note="P -> L (in TBRS; somatic mutation;
FT                   dbSNP:rs772368909)"
FT                   /evidence="ECO:0000269|PubMed:24614070"
FT                   /id="VAR_071468"
FT   VARIANT         731
FT                   /note="Missing (in a patient with chronic myelomonocytic
FT                   leukemia)"
FT                   /evidence="ECO:0000269|PubMed:21828135"
FT                   /id="VAR_067235"
FT   VARIANT         749
FT                   /note="R -> C (in TBRS; somatic mutation;
FT                   dbSNP:rs754613602)"
FT                   /evidence="ECO:0000269|PubMed:24614070"
FT                   /id="VAR_071469"
FT   VARIANT         771
FT                   /note="R -> Q (in TBRS; unknown pathological significance;
FT                   dbSNP:rs757823678)"
FT                   /evidence="ECO:0000269|PubMed:27701732"
FT                   /id="VAR_077524"
FT   VARIANT         778
FT                   /note="V -> G (in TBRS; unknown pathological significance;
FT                   dbSNP:rs979932565)"
FT                   /evidence="ECO:0000269|PubMed:27317772"
FT                   /id="VAR_077525"
FT   VARIANT         838
FT                   /note="N -> D (in TBRS; somatic mutation;
FT                   dbSNP:rs961377711)"
FT                   /evidence="ECO:0000269|PubMed:24614070"
FT                   /id="VAR_071470"
FT   VARIANT         882
FT                   /note="R -> C (in TBRS and AML; somatic variant in AML;
FT                   dbSNP:rs377577594)"
FT                   /evidence="ECO:0000269|PubMed:21067377,
FT                   ECO:0000269|PubMed:21828135, ECO:0000269|PubMed:28432085,
FT                   ECO:0000269|PubMed:28941052"
FT                   /id="VAR_067236"
FT   VARIANT         882
FT                   /note="R -> H (in TBRS and AML; somatic variant in AML;
FT                   dbSNP:rs147001633)"
FT                   /evidence="ECO:0000269|PubMed:21067377,
FT                   ECO:0000269|PubMed:21828135, ECO:0000269|PubMed:27991732,
FT                   ECO:0000269|PubMed:28941052"
FT                   /id="VAR_067237"
FT   VARIANT         882
FT                   /note="R -> P (in a patient with chronic myelomonocytic
FT                   leukemia; somatic mutation; dbSNP:rs147001633)"
FT                   /evidence="ECO:0000269|PubMed:21828135"
FT                   /id="VAR_067238"
FT   VARIANT         902
FT                   /note="F -> S (in TBRS; somatic mutation;
FT                   dbSNP:rs587777510)"
FT                   /evidence="ECO:0000269|PubMed:24614070"
FT                   /id="VAR_071471"
FT   VARIANT         904
FT                   /note="P -> L (in TBRS; somatic mutation;
FT                   dbSNP:rs149095705)"
FT                   /evidence="ECO:0000269|PubMed:24614070"
FT                   /id="VAR_071472"
FT   MUTAGEN         732
FT                   /note="F->A: Loss of activity due to the incapacity to bind
FT                   the regulatory subunit DNMT3L."
FT                   /evidence="ECO:0000269|PubMed:17713477"
FT   STRAND          295..298
FT                   /evidence="ECO:0007829|PDB:3LLR"
FT   STRAND          306..311
FT                   /evidence="ECO:0007829|PDB:3LLR"
FT   HELIX           313..315
FT                   /evidence="ECO:0007829|PDB:3LLR"
FT   STRAND          325..330
FT                   /evidence="ECO:0007829|PDB:3LLR"
FT   TURN            331..333
FT                   /evidence="ECO:0007829|PDB:3LLR"
FT   STRAND          336..340
FT                   /evidence="ECO:0007829|PDB:3LLR"
FT   HELIX           341..343
FT                   /evidence="ECO:0007829|PDB:3LLR"
FT   STRAND          344..346
FT                   /evidence="ECO:0007829|PDB:3LLR"
FT   HELIX           347..349
FT                   /evidence="ECO:0007829|PDB:3LLR"
FT   HELIX           350..353
FT                   /evidence="ECO:0007829|PDB:3LLR"
FT   HELIX           356..361
FT                   /evidence="ECO:0007829|PDB:3LLR"
FT   HELIX           363..380
FT                   /evidence="ECO:0007829|PDB:3LLR"
FT   HELIX           393..395
FT                   /evidence="ECO:0007829|PDB:3LLR"
FT   HELIX           399..411
FT                   /evidence="ECO:0007829|PDB:3LLR"
FT   TURN            415..417
FT                   /evidence="ECO:0007829|PDB:3LLR"
FT   HELIX           419..422
FT                   /evidence="ECO:0007829|PDB:3LLR"
FT   HELIX           476..484
FT                   /evidence="ECO:0007829|PDB:4QBS"
FT   HELIX           490..492
FT                   /evidence="ECO:0007829|PDB:4QBS"
FT   TURN            495..497
FT                   /evidence="ECO:0007829|PDB:4QBS"
FT   STRAND          502..505
FT                   /evidence="ECO:0007829|PDB:4QBS"
FT   STRAND          507..514
FT                   /evidence="ECO:0007829|PDB:4QBS"
FT   HELIX           515..524
FT                   /evidence="ECO:0007829|PDB:4QBS"
FT   STRAND          532..536
FT                   /evidence="ECO:0007829|PDB:4QBS"
FT   TURN            538..540
FT                   /evidence="ECO:0007829|PDB:4QBS"
FT   STRAND          544..548
FT                   /evidence="ECO:0007829|PDB:4QBS"
FT   TURN            552..554
FT                   /evidence="ECO:0007829|PDB:4QBR"
FT   STRAND          557..559
FT                   /evidence="ECO:0007829|PDB:4QBS"
FT   HELIX           560..566
FT                   /evidence="ECO:0007829|PDB:4QBS"
FT   HELIX           571..577
FT                   /evidence="ECO:0007829|PDB:4QBS"
FT   STRAND          578..580
FT                   /evidence="ECO:0007829|PDB:4QBS"
FT   TURN            584..586
FT                   /evidence="ECO:0007829|PDB:4QBS"
FT   STRAND          587..589
FT                   /evidence="ECO:0007829|PDB:4QBQ"
FT   STRAND          595..597
FT                   /evidence="ECO:0007829|PDB:4QBS"
FT   HELIX           601..608
FT                   /evidence="ECO:0007829|PDB:4QBS"
FT   HELIX           628..630
FT                   /evidence="ECO:0007829|PDB:4U7T"
FT   STRAND          634..639
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   TURN            642..644
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   HELIX           645..652
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   STRAND          657..663
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   HELIX           667..676
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   TURN            677..679
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   STRAND          681..683
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   HELIX           687..689
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   HELIX           692..698
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   STRAND          702..706
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   TURN            711..713
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   TURN            722..724
FT                   /evidence="ECO:0007829|PDB:2QRV"
FT   HELIX           728..730
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   HELIX           731..741
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   STRAND          752..761
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   HELIX           763..773
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   STRAND          778..781
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   HELIX           782..784
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   STRAND          786..788
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   STRAND          791..796
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   TURN            799..802
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   HELIX           815..818
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   STRAND          824..826
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   STRAND          828..830
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   HELIX           837..840
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   TURN            843..846
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   STRAND          849..852
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   STRAND          855..857
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   HELIX           861..868
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   TURN            872..875
FT                   /evidence="ECO:0007829|PDB:2QRV"
FT   HELIX           882..891
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   HELIX           895..902
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   HELIX           903..905
FT                   /evidence="ECO:0007829|PDB:5YX2"
FT   TURN            906..908
FT                   /evidence="ECO:0007829|PDB:5YX2"
SQ   SEQUENCE   912 AA;  101858 MW;  BD1FF7C5B4F54A33 CRC64;
     MPAMPSSGPG DTSSSAAERE EDRKDGEEQE EPRGKEERQE PSTTARKVGR PGRKRKHPPV
     ESGDTPKDPA VISKSPSMAQ DSGASELLPN GDLEKRSEPQ PEEGSPAGGQ KGGAPAEGEG
     AAETLPEASR AVENGCCTPK EGRGAPAEAG KEQKETNIES MKMEGSRGRL RGGLGWESSL
     RQRPMPRLTF QAGDPYYISK RKRDEWLARW KREAEKKAKV IAGMNAVEEN QGPGESQKVE
     EASPPAVQQP TDPASPTVAT TPEPVGSDAG DKNATKAGDD EPEYEDGRGF GIGELVWGKL
     RGFSWWPGRI VSWWMTGRSR AAEGTRWVMW FGDGKFSVVC VEKLMPLSSF CSAFHQATYN
     KQPMYRKAIY EVLQVASSRA GKLFPVCHDS DESDTAKAVE VQNKPMIEWA LGGFQPSGPK
     GLEPPEEEKN PYKEVYTDMW VEPEAAAYAP PPPAKKPRKS TAEKPKVKEI IDERTRERLV
     YEVRQKCRNI EDICISCGSL NVTLEHPLFV GGMCQNCKNC FLECAYQYDD DGYQSYCTIC
     CGGREVLMCG NNNCCRCFCV ECVDLLVGPG AAQAAIKEDP WNCYMCGHKG TYGLLRRRED
     WPSRLQMFFA NNHDQEFDPP KVYPPVPAEK RKPIRVLSLF DGIATGLLVL KDLGIQVDRY
     IASEVCEDSI TVGMVRHQGK IMYVGDVRSV TQKHIQEWGP FDLVIGGSPC NDLSIVNPAR
     KGLYEGTGRL FFEFYRLLHD ARPKEGDDRP FFWLFENVVA MGVSDKRDIS RFLESNPVMI
     DAKEVSAAHR ARYFWGNLPG MNRPLASTVN DKLELQECLE HGRIAKFSKV RTITTRSNSI
     KQGKDQHFPV FMNEKEDILW CTEMERVFGF PVHYTDVSNM SRLARQRLLG RSWSVPVIRH
     LFAPLKEYFA CV
//
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