ID DNM3A_MOUSE Reviewed; 908 AA. AC O88508; Q3TZK8; Q3UH24; Q8CJ60; Q922J0; Q9CSE1; DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-2000, sequence version 2. DT 27-MAR-2024, entry version 212. DE RecName: Full=DNA (cytosine-5)-methyltransferase 3A; DE Short=Dnmt3a; DE EC=2.1.1.37 {ECO:0000269|PubMed:11399089, ECO:0000269|PubMed:9662389}; DE AltName: Full=Cysteine methyltransferase DNMT3A {ECO:0000305}; DE EC=2.1.1.- {ECO:0000269|PubMed:21481189}; DE AltName: Full=DNA methyltransferase MmuIIIA; DE Short=DNA MTase MmuIIIA; DE Short=M.MmuIIIA; GN Name=Dnmt3a {ECO:0000303|PubMed:12138111, GN ECO:0000312|MGI:MGI:1261827}; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=9662389; DOI=10.1038/890; RA Okano M., Xie S., Li E.; RT "Cloning and characterization of a family of novel mammalian DNA (cytosine- RT 5) methyltransferases."; RL Nat. Genet. 19:219-220(1998). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Mammary gland; 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 [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC STRAIN=C57BL/6J; TISSUE=Brain, Embryo, and Skin; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), SUBCELLULAR LOCATION, ALTERNATIVE RP PROMOTER USAGE, AND TISSUE SPECIFICITY. RC STRAIN=129/SvJ; 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 [5] RP FUNCTION, AND DEVELOPMENTAL STAGE. RX PubMed=10555141; DOI=10.1016/s0092-8674(00)81656-6; RA Okano M., Bell D.W., Haber D.A., Li E.; RT "DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo RT methylation and mammalian development."; RL Cell 99:247-257(1999). RN [6] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=11399089; DOI=10.1006/jmbi.2001.4710; RA Gowher H., Jeltsch A.; RT "Enzymatic properties of recombinant Dnmt3a DNA methyltransferase from RT mouse: the enzyme modifies DNA in a non-processive manner and also RT methylates non-CpG correction sites."; RL J. Mol. Biol. 309:1201-1208(2001). RN [7] RP ERRATUM OF PUBMED:11399089. RA Gowher H., Jeltsch A.; RL J. Mol. Biol. 310:951-951(2001). RN [8] RP FUNCTION, AND INTERACTION WITH ZBTB18 AND HDAC1. RX PubMed=11350943; DOI=10.1093/emboj/20.10.2536; RA Fuks F., Burgers W.A., Godin N., Kasai M., Kouzarides T.; RT "Dnmt3a binds deacetylases and is recruited by a sequence-specific RT repressor to silence transcription."; RL EMBO J. 20:2536-2544(2001). RN [9] RP FUNCTION. RX PubMed=11919202; DOI=10.1074/jbc.m202148200; RA Gowher H., Jeltsch A.; RT "Molecular enzymology of the catalytic domains of the Dnmt3a and Dnmt3b DNA RT methyltransferases."; RL J. Biol. Chem. 277:20409-20414(2002). RN [10] RP IDENTIFICATION IN A COMPLEX WITH HDAC1. RX PubMed=12616525; DOI=10.1002/jcb.10457; RA Datta J., Ghoshal K., Sharma S.M., Tajima S., Jacob S.T.; RT "Biochemical fractionation reveals association of DNA methyltransferase RT (Dnmt) 3b with Dnmt1 and that of Dnmt 3a with a histone H3 RT methyltransferase and Hdac1."; RL J. Cell. Biochem. 88:855-864(2003). RN [11] RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF 302-VAL-PRO-303 AND RP 705-PRO-CYS-706. RX PubMed=15456878; DOI=10.1128/mcb.24.20.9048-9058.2004; RA Chen T., Tsujimoto N., Li E.; RT "The PWWP domain of Dnmt3a and Dnmt3b is required for directing DNA RT methylation to the major satellite repeats at pericentric RT heterochromatin."; RL Mol. Cell. Biol. 24:9048-9058(2004). RN [12] RP FUNCTION. RX PubMed=15215868; DOI=10.1038/nature02633; RA Kaneda M., Okano M., Hata K., Sado T., Tsujimoto N., Li E., Sasaki H.; RT "Essential role for de novo DNA methyltransferase Dnmt3a in paternal and RT maternal imprinting."; RL Nature 429:900-903(2004). RN [13] RP SUMOYLATION, AND INTERACTION WITH UBC9; PIAS1 AND PIAS2. RX PubMed=14752048; DOI=10.1093/nar/gkh195; RA Ling Y., Sankpal U.T., Robertson A.K., McNally J.G., Karpova T., RA Robertson K.D.; RT "Modification of de novo DNA methyltransferase 3a (Dnmt3a) by SUMO-1 RT modulates its interaction with histone deacetylases (HDACs) and its RT capacity to repress transcription."; RL Nucleic Acids Res. 32:598-610(2004). RN [14] RP ACTIVITY REGULATION. RX PubMed=15671018; DOI=10.1074/jbc.m413412200; RA Gowher H., Liebert K., Hermann A., Xu G., Jeltsch A.; RT "Mechanism of stimulation of catalytic activity of Dnmt3A and Dnmt3B DNA- RT (cytosine-C5)-methyltransferases by Dnmt3L."; RL J. Biol. Chem. 280:13341-13348(2005). RN [15] RP FUNCTION. RX PubMed=16567415; DOI=10.1093/jb/mvj044; RA Takeshima H., Suetake I., Shimahara H., Ura K., Tate S., Tajima S.; RT "Distinct DNA methylation activity of Dnmt3a and Dnmt3b towards naked and RT nucleosomal DNA."; RL J. Biochem. 139:503-515(2006). RN [16] RP MUTAGENESIS OF PHE-636; GLU-660; ASP-682; CYS-706; ASN-707; SER-710; RP ARG-716; LYS-717; GLU-752; ASN-753; ARG-788; ARG-827; ARG-832; ARG-878; RP ARG-881 AND ARG-883. RX PubMed=16472822; DOI=10.1016/j.jmb.2006.01.035; RA Gowher H., Loutchanwoot P., Vorobjeva O., Handa V., Jurkowska R.Z., RA Jurkowski T.P., Jeltsch A.; RT "Mutational analysis of the catalytic domain of the murine Dnmt3a DNA- RT (cytosine C5)-methyltransferase."; RL J. Mol. Biol. 357:928-941(2006). RN [17] RP 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 [18] 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 [19] RP FUNCTION, ACTIVITY REGULATION, AND MUTAGENESIS OF PHE-728. 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 [20] RP FUNCTION. RX PubMed=18823905; DOI=10.1016/j.jmb.2008.03.001; RA Takeshima H., Suetake I., Tajima S.; RT "Mouse Dnmt3a preferentially methylates linker DNA and is inhibited by RT histone H1."; RL J. Mol. Biol. 383:810-821(2008). RN [21] RP INTERACTION WITH UHRF1. RX PubMed=19798101; DOI=10.1038/embor.2009.201; RA Meilinger D., Fellinger K., Bultmann S., Rothbauer U., Bonapace I.M., RA Klinkert W.E., Spada F., Leonhardt H.; RT "Np95 interacts with de novo DNA methyltransferases, Dnmt3a and Dnmt3b, and RT mediates epigenetic silencing of the viral CMV promoter in embryonic stem RT cells."; RL EMBO Rep. 10:1259-1264(2009). RN [22] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-102; THR-257; SER-386 AND RP SER-389, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Kidney, Spleen, and Testis; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [23] RP FUNCTION, SUBCELLULAR LOCATION, AND DOMAIN. RX PubMed=20547484; DOI=10.1074/jbc.m109.089433; RA Dhayalan A., Rajavelu A., Rathert P., Tamas R., Jurkowska R.Z., Ragozin S., RA Jeltsch A.; RT "The Dnmt3a PWWP domain reads histone 3 lysine 36 trimethylation and guides RT DNA methylation."; RL J. Biol. Chem. 285:26114-26120(2010). RN [24] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, METHYLATION AT CYS-706, RP AND MUTAGENESIS OF CYS-706. RX PubMed=21481189; DOI=10.1111/j.1742-4658.2011.08121.x; RA Siddique A.N., Jurkowska R.Z., Jurkowski T.P., Jeltsch A.; RT "Auto-methylation of the mouse DNA-(cytosine C5)-methyltransferase Dnmt3a RT at its active site cysteine residue."; RL FEBS J. 278:2055-2063(2011). RN [25] RP METHYLATION [LARGE SCALE ANALYSIS] AT ARG-167, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Embryo; RX PubMed=24129315; DOI=10.1074/mcp.o113.027870; RA Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M., RA Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V., RA Bedford M.T., Comb M.J.; RT "Immunoaffinity enrichment and mass spectrometry analysis of protein RT methylation."; RL Mol. Cell. Proteomics 13:372-387(2014). RN [26] RP MUTAGENESIS OF TRP-293; ILE-306 AND TRP-326. 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 [27] RP INTERACTION WITH SPOCD1. RX PubMed=32674113; DOI=10.1038/s41586-020-2557-5; RA Zoch A., Auchynnikava T., Berrens R.V., Kabayama Y., Schoepp T., Heep M., RA Vasiliauskaite L., Perez-Rico Y.A., Cook A.G., Shkumatava A., RA Rappsilber J., Allshire R.C., O'Carroll D.; RT "SPOCD1 is an essential executor of piRNA-directed de novo DNA RT methylation."; RL Nature 584:635-639(2020). CC -!- FUNCTION: Required for genome-wide de novo methylation and is essential CC for the establishment of DNA methylation patterns during development CC (PubMed:9662389, PubMed:11399089, PubMed:10555141, PubMed:11919202, CC PubMed:16567415, PubMed:17713477). DNA methylation is coordinated with CC methylation of histones (PubMed:9662389, PubMed:11399089, CC PubMed:10555141, PubMed:11919202, PubMed:16567415, PubMed:17713477). It CC modifies DNA in a non-processive manner and also methylates non-CpG CC sites (PubMed:9662389, PubMed:11399089, PubMed:10555141, CC PubMed:11919202, PubMed:16567415, PubMed:17713477). May preferentially CC methylate DNA linker between 2 nucleosomal cores and is inhibited by CC histone H1 (PubMed:18823905). Plays a role in paternal and maternal CC imprinting (PubMed:15215868). Required for methylation of most CC imprinted loci in germ cells (PubMed:15215868). Acts as a CC transcriptional corepressor for ZBTB18 (PubMed:11350943). Recruited to CC trimethylated 'Lys-36' of histone H3 (H3K36me3) sites CC (PubMed:20547484). Can actively repress transcription through the CC recruitment of HDAC activity (PubMed:11350943). Also has weak auto- CC methylation activity on Cys-706 in absence of DNA (PubMed:21481189). CC {ECO:0000269|PubMed:10555141, ECO:0000269|PubMed:11350943, CC ECO:0000269|PubMed:11399089, ECO:0000269|PubMed:11919202, CC ECO:0000269|PubMed:15215868, ECO:0000269|PubMed:16567415, CC ECO:0000269|PubMed:17713477, ECO:0000269|PubMed:18823905, CC ECO:0000269|PubMed:20547484, ECO:0000269|PubMed:21481189, CC ECO:0000269|PubMed:9662389}. 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:11399089, ECO:0000269|PubMed:9662389}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:13682; CC Evidence={ECO:0000269|PubMed:11399089, ECO:0000269|PubMed:9662389}; 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:0000269|PubMed:21481189}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66545; CC Evidence={ECO:0000269|PubMed:21481189}; CC -!- ACTIVITY REGULATION: Activated by binding to the regulatory factor CC DNMT3L (PubMed:15671018, PubMed:17713477, PubMed:21481189). Auto- CC methylation at Cys-706 in absence of DNA inactivates the DNA CC methyltransferase activity (PubMed:21481189). CC {ECO:0000269|PubMed:15671018, ECO:0000269|PubMed:17713477, CC ECO:0000269|PubMed:21481189}. CC -!- SUBUNIT: Heterotetramer composed of 1 DNMT3A homodimer and 2 DNMT3L CC subunits (DNMT3L-DNMT3A-DNMT3A-DNMT3L) (By similarity). Interacts with CC DNMT1 and DNMT3B (By similarity). Interacts with MPHOSPH8 (By CC similarity). Interacts with histone H3 that is not methylated at 'Lys- CC 4' (H3K4) (By similarity). Binds the ZBTB18 transcriptional repressor CC (PubMed:11350943). Interacts with SETDB1 (By similarity). Associates CC with HDAC1 through its ADD domain (PubMed:11350943, PubMed:12616525). CC Interacts with UHRF1 (PubMed:19798101). Interacts with the PRC2/EED- CC EZH2 complex (PubMed:16357870). Interacts with UBC9, PIAS1 and PIAS2 CC (PubMed:14752048). Interacts with SPOCD1 (PubMed:32674113). Interacts CC with ZNF263; recruited to the SIX3 promoter along with other proteins CC involved in chromatin modification and transcriptional corepression CC where it contributes to transcriptional repression (By similarity). CC {ECO:0000250|UniProtKB:Q9Y6K1, ECO:0000269|PubMed:11350943, CC ECO:0000269|PubMed:12616525, ECO:0000269|PubMed:14752048, CC ECO:0000269|PubMed:16357870, ECO:0000269|PubMed:19798101, CC ECO:0000269|PubMed:32674113}. CC -!- INTERACTION: CC O88508; Q9CWR8: Dnmt3l; NbExp=6; IntAct=EBI-995154, EBI-3043871; CC O88508; Q60848: Hells; NbExp=4; IntAct=EBI-995154, EBI-3043887; CC O88508; P51608-1: MECP2; Xeno; NbExp=10; IntAct=EBI-995154, EBI-26687319; CC O88508-1; Q9CWR8: Dnmt3l; NbExp=6; IntAct=EBI-15650457, EBI-3043871; CC O88508-1; Q9Z148-2: Ehmt2; NbExp=3; IntAct=EBI-15650457, EBI-15737169; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:12138111, CC ECO:0000269|PubMed:15456878, ECO:0000269|PubMed:20547484}. Chromosome CC {ECO:0000269|PubMed:20547484}. Cytoplasm CC {ECO:0000250|UniProtKB:Q9Y6K1}. Note=Accumulates in the major satellite CC repeats at pericentric heterochromatin. {ECO:0000269|PubMed:20547484}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative promoter usage; Named isoforms=2; CC Name=1; CC IsoId=O88508-1; Sequence=Displayed; CC Name=2; CC IsoId=O88508-2; Sequence=VSP_009423; CC -!- TISSUE SPECIFICITY: Isoform 1 is expressed ubiquitously at low levels. CC Expression of isoform 2 is restricted to tissues containing cells which CC are undergoing active de novo methylation, including spleen, testis and CC thymus. {ECO:0000269|PubMed:12138111}. CC -!- DEVELOPMENTAL STAGE: At 7.5 dpc, the protein is moderately expressed in CC embryonic ectoderm and weakly in mesodermal cells. At 8.5 dpc and 9.5 CC dpc, the expression become ubiquitous with an increase in the somites CC and in the ventral part of the embryo. {ECO:0000269|PubMed:10555141}. 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) (PubMed:20547484). CC {ECO:0000269|PubMed:20547484}. CC -!- PTM: Auto-methylated at Cys-706: auto-methylation takes place in CC absence of DNA substrate and inactivates the DNA methyltransferase CC activity (PubMed:21481189). Inactivation by auto-methylation may be CC used to inactivate unused DNA methyltransferases in the cell CC (PubMed:21481189). {ECO:0000269|PubMed:21481189}. CC -!- PTM: Sumoylated; sumoylation disrupts the ability to interact with CC histone deacetylases (HDAC1 and HDAC2) and repress transcription. CC {ECO:0000269|PubMed:14752048}. CC -!- SIMILARITY: Belongs to the class I-like SAM-binding methyltransferase CC superfamily. C5-methyltransferase family. {ECO:0000255|PROSITE- CC ProRule:PRU01016}. CC -!- SEQUENCE CAUTION: CC Sequence=BAB28644.2; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF068625; AAC40177.2; -; mRNA. DR EMBL; AF480164; AAN40038.1; -; mRNA. DR EMBL; AK013096; BAB28644.2; ALT_INIT; mRNA. DR EMBL; AK090132; BAC41110.1; -; mRNA. DR EMBL; AK147263; BAE27806.1; -; mRNA. DR EMBL; AK147627; BAE28033.1; -; mRNA. DR EMBL; AK147642; BAE28043.1; -; mRNA. DR EMBL; AK147676; BAE28067.1; -; mRNA. DR EMBL; AK157792; BAE34200.1; -; mRNA. DR EMBL; BC007466; AAH07466.1; -; mRNA. DR CCDS; CCDS25784.1; -. [O88508-2] DR CCDS; CCDS36397.1; -. [O88508-1] DR RefSeq; NP_001258682.1; NM_001271753.1. [O88508-1] DR RefSeq; NP_031898.1; NM_007872.4. [O88508-1] DR RefSeq; NP_714965.1; NM_153743.4. [O88508-2] DR RefSeq; XP_006515016.1; XM_006514953.3. DR RefSeq; XP_006515019.1; XM_006514956.3. [O88508-1] DR PDB; 3SW9; X-ray; 3.05 A; P/Q=39-50. DR PDB; 3SWC; X-ray; 2.33 A; P/Q=39-50. DR PDBsum; 3SW9; -. DR PDBsum; 3SWC; -. DR AlphaFoldDB; O88508; -. DR SMR; O88508; -. DR BioGRID; 199261; 24. DR CORUM; O88508; -. DR DIP; DIP-38005N; -. DR IntAct; O88508; 15. DR MINT; O88508; -. DR STRING; 10090.ENSMUSP00000020991; -. DR BindingDB; O88508; -. DR ChEMBL; CHEMBL3108652; -. DR REBASE; 3747; M.MmuDnmt3A. DR iPTMnet; O88508; -. DR PhosphoSitePlus; O88508; -. DR EPD; O88508; -. DR jPOST; O88508; -. DR MaxQB; O88508; -. DR PaxDb; 10090-ENSMUSP00000020991; -. DR PeptideAtlas; O88508; -. DR ProteomicsDB; 277363; -. [O88508-1] DR ProteomicsDB; 277364; -. [O88508-2] DR Pumba; O88508; -. DR Antibodypedia; 4006; 1128 antibodies from 46 providers. DR DNASU; 13435; -. DR Ensembl; ENSMUST00000020991.15; ENSMUSP00000020991.9; ENSMUSG00000020661.16. [O88508-1] DR Ensembl; ENSMUST00000111186.8; ENSMUSP00000106817.2; ENSMUSG00000020661.16. [O88508-2] DR Ensembl; ENSMUST00000172689.8; ENSMUSP00000133543.2; ENSMUSG00000020661.16. [O88508-2] DR Ensembl; ENSMUST00000174817.8; ENSMUSP00000134009.2; ENSMUSG00000020661.16. [O88508-1] DR GeneID; 13435; -. DR KEGG; mmu:13435; -. DR UCSC; uc007mxb.1; mouse. [O88508-1] DR AGR; MGI:1261827; -. DR CTD; 1788; -. DR MGI; MGI:1261827; Dnmt3a. DR VEuPathDB; HostDB:ENSMUSG00000020661; -. DR eggNOG; ENOG502QR6U; Eukaryota. DR GeneTree; ENSGT00940000155459; -. DR HOGENOM; CLU_006958_9_1_1; -. DR InParanoid; O88508; -. DR OMA; PRCFCVE; -. DR OrthoDB; 2904336at2759; -. DR PhylomeDB; O88508; -. DR TreeFam; TF329039; -. DR BRENDA; 2.1.1.37; 3474. DR Reactome; R-MMU-212300; PRC2 methylates histones and DNA. DR Reactome; R-MMU-3214858; RMTs methylate histone arginines. DR BioGRID-ORCS; 13435; 2 hits in 81 CRISPR screens. DR ChiTaRS; Dnmt3a; mouse. DR PRO; PR:O88508; -. DR Proteomes; UP000000589; Chromosome 12. DR RNAct; O88508; Protein. DR Bgee; ENSMUSG00000020661; Expressed in urethra mesenchymal layer and 291 other cell types or tissues. DR ExpressionAtlas; O88508; baseline and differential. DR GO; GO:1902494; C:catalytic complex; ISO:MGI. DR GO; GO:0000775; C:chromosome, centromeric region; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:MGI. DR GO; GO:0000791; C:euchromatin; ISS:UniProtKB. DR GO; GO:0000792; C:heterochromatin; IDA:MGI. DR GO; GO:0016363; C:nuclear matrix; ISS:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; ISO:MGI. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0001741; C:XY body; IDA:MGI. DR GO; GO:0003682; F:chromatin binding; IDA:MGI. DR GO; GO:0003886; F:DNA (cytosine-5-)-methyltransferase activity; IDA:MGI. DR GO; GO:0051719; F:DNA (cytosine-5-)-methyltransferase activity, acting on CpN substrates; TAS:Reactome. DR GO; GO:0003677; F:DNA binding; IDA:MGI. DR GO; GO:0042802; F:identical protein binding; ISO:MGI. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0106363; F:protein-cysteine methyltransferase activity; IDA:UniProtKB. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISO:MGI. DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISO:MGI. DR GO; GO:0045322; F:unmethylated CpG binding; ISO:MGI. DR GO; GO:0141068; P:autosome genomic imprinting; IDA:BHF-UCL. DR GO; GO:0090116; P:C-5 methylation of cytosine; ISO:MGI. DR GO; GO:0071230; P:cellular response to amino acid stimulus; IDA:MGI. DR GO; GO:1903926; P:cellular response to bisphenol A; IDA:MGI. 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:MGI. DR GO; GO:0032776; P:DNA methylation on cytosine; ISO:MGI. DR GO; GO:0006346; P:DNA methylation-dependent heterochromatin formation; IDA:MGI. DR GO; GO:0071514; P:genomic imprinting; IMP:UniProtKB. DR GO; GO:0097284; P:hepatocyte apoptotic process; IEA:Ensembl. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IBA:GO_Central. DR GO; GO:0044027; P:negative regulation of gene expression via CpG island methylation; IDA:BHF-UCL. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:MGI. DR GO; GO:0030182; P:neuron differentiation; IEA:Ensembl. DR GO; GO:1900039; P:positive regulation of cellular response to hypoxia; ISO:MGI. DR GO; GO:0043045; P:post-fertilization epigenetic regulation of gene expression; IMP: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; IMP:MGI. DR CDD; cd11729; ADDz_Dnmt3a; 1. DR CDD; cd20154; PWWP_DNMT3A; 1. DR Gene3D; 2.30.30.140; -; 1. DR Gene3D; 1.10.720.50; PWWP, helical domain; 1. DR Gene3D; 3.40.50.150; Vaccinia Virus protein VP39; 2. DR IDEAL; IID50163; -. 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_GATA1-like. DR InterPro; IPR049554; DNMT3_ADD_PHD. DR InterPro; IPR000313; PWWP_dom. DR InterPro; IPR029063; SAM-dependent_MTases_sf. DR PANTHER; PTHR23068:SF10; DNA (CYTOSINE-5)-METHYLTRANSFERASE 3A; 1. DR PANTHER; PTHR23068; DNA CYTOSINE-5- -METHYLTRANSFERASE 3-RELATED; 1. DR Pfam; PF17980; ADD_DNMT3; 1. DR Pfam; PF21255; ADDz_Dnmt3b; 1. DR Pfam; PF00145; DNA_methylase; 1. DR Pfam; PF00855; PWWP; 1. DR SMART; SM00293; PWWP; 1. DR SUPFAM; SSF53335; S-adenosyl-L-methionine-dependent methyltransferases; 1. DR SUPFAM; SSF63748; Tudor/PWWP/MBT; 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. DR Genevisible; O88508; MM. PE 1: Evidence at protein level; KW 3D-structure; Alternative promoter usage; Chromatin regulator; Chromosome; KW Cytoplasm; DNA-binding; Isopeptide bond; Metal-binding; Methylation; KW Methyltransferase; Nucleus; Phosphoprotein; Reference proteome; Repressor; KW S-adenosyl-L-methionine; Transcription; Transcription regulation; KW Transferase; Ubl conjugation; Zinc; Zinc-finger. FT CHAIN 1..908 FT /note="DNA (cytosine-5)-methyltransferase 3A" FT /id="PRO_0000088044" FT DOMAIN 288..346 FT /note="PWWP" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00162" FT DOMAIN 478..610 FT /note="ADD" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00865" FT DOMAIN 630..908 FT /note="SAM-dependent MTase C5-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01016" FT ZN_FING 489..519 FT /note="GATA-type; atypical" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00865" FT ZN_FING 530..586 FT /note="PHD-type; atypical" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00865" FT REGION 1..183 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 195..399 FT /note="Interaction with DNMT1 and DNMT3B" FT /evidence="ECO:0000250" FT REGION 226..281 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 443..462 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 490..582 FT /note="Interaction with the PRC2/EED-EZH2 complex" FT /evidence="ECO:0000269|PubMed:16357870" FT COMPBIAS 12..41 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 63..80 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 226..240 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 706 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01016, FT ECO:0000255|PROSITE-ProRule:PRU10018" FT BINDING 637..641 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000250|UniProtKB:Q9Y6K1" FT BINDING 660 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000250|UniProtKB:Q9Y6K1" FT BINDING 682..684 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000250|UniProtKB:Q9Y6K1" FT BINDING 887..889 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000250|UniProtKB:Q9Y6K1" FT MOD_RES 102 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 120 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q1LZ53" FT MOD_RES 167 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES 239 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9Y6K1" FT MOD_RES 251 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9Y6K1" FT MOD_RES 257 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 386 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 389 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 706 FT /note="S-methylcysteine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:21481189" FT CROSSLNK 158 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0000250|UniProtKB:Q9Y6K1" FT VAR_SEQ 1..219 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:12138111, FT ECO:0000303|PubMed:16141072" FT /id="VSP_009423" FT MUTAGEN 293 FT /note="Missing: Decreased protein abundance." FT /evidence="ECO:0000269|PubMed:30478443" FT MUTAGEN 302..303 FT /note="WP->ST: Prevents accumulation in pericentric FT heterochromatin." FT /evidence="ECO:0000269|PubMed:15456878" FT MUTAGEN 306 FT /note="I->N: Decreased protein abundance." FT /evidence="ECO:0000269|PubMed:30478443" FT MUTAGEN 326 FT /note="W->R: The protein is stably expressed." FT /evidence="ECO:0000269|PubMed:30478443" FT MUTAGEN 636 FT /note="F->A: Reduces activity about 20-fold. Loss of FT substrate binding." FT /evidence="ECO:0000269|PubMed:16472822" FT MUTAGEN 660 FT /note="E->A: Reduces activity about 15-fold. Loss of FT substrate binding." FT /evidence="ECO:0000269|PubMed:16472822" FT MUTAGEN 682 FT /note="D->A: Strongly reduces substrate binding. No effect FT on activity." FT /evidence="ECO:0000269|PubMed:16472822" FT MUTAGEN 705..706 FT /note="PC->VD: No effect on localization." FT /evidence="ECO:0000269|PubMed:15456878" FT MUTAGEN 706 FT /note="C->A: Reduces activity about 5-fold. Reduces FT DNA-binding capacity. Abolished cysteine-methylation." FT /evidence="ECO:0000269|PubMed:16472822, FT ECO:0000269|PubMed:21481189" FT MUTAGEN 707 FT /note="N->Q: Reduces activity about 3-fold." FT /evidence="ECO:0000269|PubMed:16472822" FT MUTAGEN 710 FT /note="S->A: No effect on activity." FT /evidence="ECO:0000269|PubMed:16472822" FT MUTAGEN 716 FT /note="R->A: Reduces activity about 30-fold. Reduces FT DNA-binding capacity." FT /evidence="ECO:0000269|PubMed:16472822" FT MUTAGEN 717 FT /note="K->A: Reduces activity about 3-fold." FT /evidence="ECO:0000269|PubMed:16472822" FT MUTAGEN 728 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 MUTAGEN 752 FT /note="E->A: Reduces activity about 10-fold." FT /evidence="ECO:0000269|PubMed:16472822" FT MUTAGEN 753 FT /note="N->A: Reduces activity about 10-fold." FT /evidence="ECO:0000269|PubMed:16472822" FT MUTAGEN 788 FT /note="R->A: Reduces activity about 15-fold." FT /evidence="ECO:0000269|PubMed:16472822" FT MUTAGEN 827 FT /note="R->A: Reduces activity about 2-fold. Reduces FT DNA-binding capacity." FT /evidence="ECO:0000269|PubMed:16472822" FT MUTAGEN 832 FT /note="R->A: Reduces DNA-binding capacity. No effect on FT activity." FT /evidence="ECO:0000269|PubMed:16472822" FT MUTAGEN 878 FT /note="R->A: Reduces activity about 6-fold. Reduces FT DNA-binding capacity." FT /evidence="ECO:0000269|PubMed:16472822" FT MUTAGEN 881 FT /note="R->A: Loss of activity. Strongly reduces substrate FT binding." FT /evidence="ECO:0000269|PubMed:16472822" FT MUTAGEN 883 FT /note="R->A: Reduces activity about 3-fold. Reduces FT DNA-binding capacity." FT /evidence="ECO:0000269|PubMed:16472822" FT CONFLICT 151 FT /note="Q -> P (in Ref. 4; AAH07466)" FT /evidence="ECO:0000305" FT CONFLICT 775 FT /note="M -> T (in Ref. 3; BAB28644)" FT /evidence="ECO:0000305" FT CONFLICT 781 FT /note="V -> G (in Ref. 3; BAB28644)" FT /evidence="ECO:0000305" FT CONFLICT 791 FT /note="W -> R (in Ref. 3; BAB28644)" FT /evidence="ECO:0000305" FT CONFLICT 809 FT /note="L -> P (in Ref. 3; BAB28644)" FT /evidence="ECO:0000305" FT CONFLICT 904 FT /note="Y -> I (in Ref. 3; BAB28644)" FT /evidence="ECO:0000305" SQ SEQUENCE 908 AA; 101672 MW; 5F98D5A8092C84A5 CRC64; MPSSGPGDTS SSSLEREDDR KEGEEQEENR GKEERQEPSA TARKVGRPGR KRKHPPVESS DTPKDPAVTT KSQPMAQDSG PSDLLPNGDL EKRSEPQPEE GSPAAGQKGG APAEGEGTET PPEASRAVEN GCCVTKEGRG ASAGEGKEQK QTNIESMKME GSRGRLRGGL GWESSLRQRP MPRLTFQAGD PYYISKRKRD EWLARWKREA EKKAKVIAVM NAVEENQASG ESQKVEEASP PAVQQPTDPA SPTVATTPEP VGGDAGDKNA TKAADDEPEY EDGRGFGIGE LVWGKLRGFS WWPGRIVSWW MTGRSRAAEG TRWVMWFGDG KFSVVCVEKL MPLSSFCSAF HQATYNKQPM YRKAIYEVLQ VASSRAGKLF PACHDSDESD SGKAVEVQNK QMIEWALGGF QPSGPKGLEP PEEEKNPYKE VYTDMWVEPE AAAYAPPPPA KKPRKSTTEK PKVKEIIDER TRERLVYEVR QKCRNIEDIC ISCGSLNVTL EHPLFIGGMC QNCKNCFLEC AYQYDDDGYQ SYCTICCGGR EVLMCGNNNC CRCFCVECVD LLVGPGAAQA AIKEDPWNCY MCGHKGTYGL LRRREDWPSR LQMFFANNHD QEFDPPKVYP PVPAEKRKPI RVLSLFDGIA TGLLVLKDLG IQVDRYIASE VCEDSITVGM VRHQGKIMYV GDVRSVTQKH IQEWGPFDLV IGGSPCNDLS IVNPARKGLY EGTGRLFFEF YRLLHDARPK EGDDRPFFWL FENVVAMGVS DKRDISRFLE SNPVMIDAKE VSAAHRARYF WGNLPGMNRP LASTVNDKLE LQECLEHGRI AKFSKVRTIT TRSNSIKQGK DQHFPVFMNE KEDILWCTEM ERVFGFPVHY TDVSNMSRLA RQRLLGRSWS VPVIRHLFAP LKEYFACV //