DNM3A_HUMAN
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 03-AUG-2022, entry version 194.
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 AlphaFoldDB; Q9Y6K1; -.
DR SMR; Q9Y6K1; -.
DR BioGRID; 108125; 78.
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; 1006 antibodies from 46 providers.
DR DNASU; 1788; -.
DR Ensembl; ENST00000264709.7; ENSP00000264709.3; ENSG00000119772.19. [Q9Y6K1-1]
DR Ensembl; ENST00000321117.10; ENSP00000324375.5; ENSG00000119772.19. [Q9Y6K1-1]
DR Ensembl; ENST00000380746.8; ENSP00000370122.4; ENSG00000119772.19. [Q9Y6K1-2]
DR Ensembl; ENST00000406659.3; ENSP00000384852.3; ENSG00000119772.19. [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; 14 hits in 1084 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 sural nerve and 143 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:0032776; P:DNA methylation on cytosine; IBA:GO_Central.
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:0045892; P:negative regulation of transcription, DNA-templated; IBA:GO_Central.
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 genomic 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 Gene3D; 3.40.50.150; -; 2.
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_sf.
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; Intellectual disability; Isopeptide bond; Metal-binding;
KW Methylation; Methyltransferase; Nucleus; Phosphoprotein;
KW Reference proteome; Repressor; S-adenosyl-L-methionine; Transferase;
KW 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 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 641..645
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:17713477,
FT ECO:0007744|PDB:2QRV"
FT BINDING 664
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:17713477,
FT ECO:0007744|PDB:2QRV"
FT BINDING 686..688
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:17713477,
FT ECO:0007744|PDB:2QRV"
FT BINDING 891..893
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
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..640
FT /evidence="ECO:0007829|PDB:6W8B"
FT TURN 642..644
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 645..652
FT /evidence="ECO:0007829|PDB:6W8B"
FT STRAND 657..663
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 667..676
FT /evidence="ECO:0007829|PDB:6W8B"
FT TURN 677..679
FT /evidence="ECO:0007829|PDB:6W8B"
FT STRAND 681..683
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 687..689
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 692..698
FT /evidence="ECO:0007829|PDB:6W8B"
FT STRAND 702..706
FT /evidence="ECO:0007829|PDB:6W8B"
FT TURN 711..713
FT /evidence="ECO:0007829|PDB:6W8B"
FT TURN 722..724
FT /evidence="ECO:0007829|PDB:2QRV"
FT TURN 726..729
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 730..741
FT /evidence="ECO:0007829|PDB:6W8B"
FT STRAND 752..761
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 763..773
FT /evidence="ECO:0007829|PDB:6W8B"
FT STRAND 778..781
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 782..784
FT /evidence="ECO:0007829|PDB:6W8B"
FT STRAND 786..788
FT /evidence="ECO:0007829|PDB:6W8B"
FT STRAND 791..796
FT /evidence="ECO:0007829|PDB:6W8B"
FT TURN 799..802
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 815..818
FT /evidence="ECO:0007829|PDB:6W8B"
FT STRAND 824..826
FT /evidence="ECO:0007829|PDB:6W8B"
FT STRAND 828..830
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 837..839
FT /evidence="ECO:0007829|PDB:6W8B"
FT STRAND 840..842
FT /evidence="ECO:0007829|PDB:6W8D"
FT TURN 843..846
FT /evidence="ECO:0007829|PDB:6W8B"
FT STRAND 849..852
FT /evidence="ECO:0007829|PDB:6W8B"
FT STRAND 855..857
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 861..868
FT /evidence="ECO:0007829|PDB:6W8B"
FT TURN 872..875
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 882..890
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 895..902
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 903..907
FT /evidence="ECO:0007829|PDB:6W8B"
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
