DNM3A_MOUSE
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 03-AUG-2022, entry version 203.
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, 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};
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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. [O88508-1]
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; O88508; -.
DR PeptideAtlas; O88508; -.
DR PRIDE; O88508; -.
DR ProteomicsDB; 277363; -. [O88508-1]
DR ProteomicsDB; 277364; -. [O88508-2]
DR Antibodypedia; 4006; 1006 antibodies from 46 providers.
DR DNASU; 13435; -.
DR Ensembl; ENSMUST00000020991; ENSMUSP00000020991; ENSMUSG00000020661. [O88508-1]
DR Ensembl; ENSMUST00000111186; ENSMUSP00000106817; ENSMUSG00000020661. [O88508-2]
DR Ensembl; ENSMUST00000172689; ENSMUSP00000133543; ENSMUSG00000020661. [O88508-2]
DR Ensembl; ENSMUST00000174817; ENSMUSP00000134009; ENSMUSG00000020661. [O88508-1]
DR GeneID; 13435; -.
DR KEGG; mmu:13435; -.
DR UCSC; uc007mxb.1; mouse. [O88508-1]
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; DGKFSVX; -.
DR OrthoDB; 1015783at2759; -.
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 75 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 287 other tissues.
DR ExpressionAtlas; O88508; baseline and differential.
DR Genevisible; O88508; MM.
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:0008168; F:methyltransferase activity; TAS:MGI.
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:0007568; P:aging; IEA:Ensembl.
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:0043045; P:DNA methylation involved in embryo development; IMP:UniProtKB.
DR GO; GO:0043046; P:DNA methylation involved in gamete generation; IMP:UniProtKB.
DR GO; GO:0032776; P:DNA methylation on cytosine; ISO:MGI.
DR GO; GO:0006346; P:DNA methylation-dependent heterochromatin assembly; IDA:MGI.
DR GO; GO:0097284; P:hepatocyte apoptotic process; IEA:Ensembl.
DR GO; GO:0044027; P:hypermethylation of CpG island; IDA:BHF-UCL.
DR GO; GO:0010216; P:maintenance of DNA methylation; TAS:BHF-UCL.
DR GO; GO:0000278; P:mitotic cell cycle; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:MGI.
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; ISO:MGI.
DR GO; GO:0006349; P:regulation of gene expression by genomic imprinting; IDA:BHF-UCL.
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 Gene3D; 3.40.50.150; -; 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.
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; 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 DNA-
FT 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 DNA-
FT 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 DNA-
FT 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 DNA-
FT 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 DNA-
FT 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
