ID DNM3A_RAT Reviewed; 908 AA. AC Q1LZ53; Q1LZ52; DT 15-JAN-2008, integrated into UniProtKB/Swiss-Prot. DT 30-MAY-2006, sequence version 1. DT 27-MAR-2024, entry version 129. DE RecName: Full=DNA (cytosine-5)-methyltransferase 3A; DE Short=Dnmt3a; DE EC=2.1.1.37 {ECO:0000250|UniProtKB:O88508}; DE AltName: Full=Cysteine methyltransferase DNMT3A {ECO:0000305}; DE EC=2.1.1.- {ECO:0000250|UniProtKB:O88508}; GN Name=Dnmt3a; OS Rattus norvegicus (Rat). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Rattus. OX NCBI_TaxID=10116; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2). RX PubMed=15203217; DOI=10.1016/j.ygeno.2004.02.004; RA Lees-Murdock D.J., McLoughlin G.A., McDaid J.R., Quinn L.M., O'Doherty A., RA Hiripi L., Hack C.J., Walsh C.P.; RT "Identification of 11 pseudogenes in the DNA methyltransferase gene family RT in rodents and humans and implications for the functional loci."; RL Genomics 84:193-204(2004). RN [2] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-102; THR-120; SER-239 AND RP SER-251, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22673903; DOI=10.1038/ncomms1871; RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C., RA Olsen J.V.; RT "Quantitative maps of protein phosphorylation sites across 14 different rat RT organs and tissues."; RL Nat. Commun. 3:876-876(2012). CC -!- FUNCTION: Required for genome-wide de novo methylation and is essential CC for the establishment of DNA methylation patterns during development. CC DNA methylation is coordinated with methylation of histones. It CC modifies DNA in a non-processive manner and also methylates non-CpG CC sites. May preferentially methylate DNA linker between 2 nucleosomal CC cores and is inhibited by histone H1. Plays a role in paternal and CC maternal imprinting. Required for methylation of most imprinted loci in CC germ cells. Acts as a transcriptional corepressor for ZBTB18. Recruited CC to trimethylated 'Lys-36' of histone H3 (H3K36me3) sites. Can actively CC repress transcription through the recruitment of HDAC activity (By CC similarity). Also has weak auto-methylation activity on Cys-706 in CC absence of DNA (By similarity). {ECO:0000250|UniProtKB:O88508}. 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:0000250|UniProtKB:O88508, ECO:0000255|PROSITE- CC ProRule:PRU10018}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:13682; CC Evidence={ECO:0000250|UniProtKB:O88508}; 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-706 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) (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 (By similarity). Interacts with SETDB1 (By similarity). Associates with CC HDAC1 through its ADD domain. Interacts with UHRF1. Interacts with the CC PRC2/EED-EZH2 complex. Interacts with UBC9, PIAS1 and PIAS2. Interacts CC with SPOCD1 (By similarity). Interacts with ZNF263; recruited to the CC SIX3 promoter along with other proteins involved in chromatin CC modification and transcriptional corepression where it contributes to CC transcriptional repression (By similarity). CC {ECO:0000250|UniProtKB:O88508, ECO:0000250|UniProtKB:Q9Y6K1}. CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q9Y6K1}. CC Chromosome {ECO:0000250|UniProtKB:Q9Y6K1}. Cytoplasm CC {ECO:0000250|UniProtKB:Q9Y6K1}. Note=Accumulates in the major satellite CC repeats at pericentric heterochromatin. {ECO:0000250|UniProtKB:O88508}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative promoter usage; Named isoforms=2; CC Name=1; CC IsoId=Q1LZ53-1; Sequence=Displayed; CC Name=2; CC IsoId=Q1LZ53-2; Sequence=VSP_029986; 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). {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-706: 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 -!- SIMILARITY: Belongs to the class I-like SAM-binding methyltransferase CC superfamily. C5-methyltransferase family. {ECO:0000255|PROSITE- CC ProRule:PRU01016}. 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; BN000395; CAE52317.1; -; mRNA. DR EMBL; BN000396; CAE52318.1; -; mRNA. DR RefSeq; NP_001003957.1; NM_001003957.1. [Q1LZ53-2] DR RefSeq; NP_001003958.1; NM_001003958.1. [Q1LZ53-1] DR RefSeq; XP_017449755.1; XM_017594266.1. [Q1LZ53-1] DR RefSeq; XP_017449756.1; XM_017594267.1. [Q1LZ53-1] DR RefSeq; XP_017449757.1; XM_017594268.1. [Q1LZ53-1] DR AlphaFoldDB; Q1LZ53; -. DR SMR; Q1LZ53; -. DR STRING; 10116.ENSRNOP00000046524; -. DR iPTMnet; Q1LZ53; -. DR PhosphoSitePlus; Q1LZ53; -. DR PaxDb; 10116-ENSRNOP00000046524; -. DR Ensembl; ENSRNOT00000047210.4; ENSRNOP00000046524.2; ENSRNOG00000026649.7. [Q1LZ53-1] DR Ensembl; ENSRNOT00055032178; ENSRNOP00055026036; ENSRNOG00055018869. [Q1LZ53-1] DR Ensembl; ENSRNOT00060020251; ENSRNOP00060015918; ENSRNOG00060011954. [Q1LZ53-1] DR Ensembl; ENSRNOT00065037256; ENSRNOP00065030062; ENSRNOG00065021888. [Q1LZ53-1] DR GeneID; 444984; -. DR KEGG; rno:444984; -. DR AGR; RGD:1303336; -. DR CTD; 1788; -. DR RGD; 1303336; Dnmt3a. DR eggNOG; ENOG502QR6U; Eukaryota. DR GeneTree; ENSGT00940000155459; -. DR InParanoid; Q1LZ53; -. DR OMA; PRCFCVE; -. DR OrthoDB; 2904336at2759; -. DR PhylomeDB; Q1LZ53; -. DR TreeFam; TF329039; -. DR Reactome; R-RNO-212300; PRC2 methylates histones and DNA. DR Reactome; R-RNO-3214858; RMTs methylate histone arginines. DR PRO; PR:Q1LZ53; -. DR Proteomes; UP000002494; Chromosome 6. DR Bgee; ENSRNOG00000026649; Expressed in skeletal muscle tissue and 18 other cell types or tissues. DR GO; GO:1902494; C:catalytic complex; ISO:RGD. DR GO; GO:0000775; C:chromosome, centromeric region; ISO:RGD. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0000791; C:euchromatin; ISS:UniProtKB. DR GO; GO:0000792; C:heterochromatin; ISO:RGD. DR GO; GO:0016363; C:nuclear matrix; ISS:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. DR GO; GO:0001741; C:XY body; ISO:RGD. DR GO; GO:0003682; F:chromatin binding; IDA:RGD. DR GO; GO:0003886; F:DNA (cytosine-5-)-methyltransferase activity; ISS:UniProtKB. DR GO; GO:0003677; F:DNA binding; ISS:UniProtKB. DR GO; GO:0042802; F:identical protein binding; ISO:RGD. 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; ISO:RGD. DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISO:RGD. DR GO; GO:0045322; F:unmethylated CpG binding; ISO:RGD. DR GO; GO:0141068; P:autosome genomic imprinting; ISO:RGD. DR GO; GO:0090116; P:C-5 methylation of cytosine; ISO:RGD. DR GO; GO:0071230; P:cellular response to amino acid stimulus; ISO:RGD. DR GO; GO:1903926; P:cellular response to bisphenol A; ISO:RGD. DR GO; GO:0071361; P:cellular response to ethanol; IEP:RGD. DR GO; GO:0071456; P:cellular response to hypoxia; IEP:RGD. DR GO; GO:0006306; P:DNA methylation; ISS:UniProtKB. DR GO; GO:0032776; P:DNA methylation on cytosine; IDA:RGD. DR GO; GO:0006346; P:DNA methylation-dependent heterochromatin formation; ISO:RGD. DR GO; GO:0071514; P:genomic imprinting; ISO:RGD. DR GO; GO:0097284; P:hepatocyte apoptotic process; IEP:RGD. 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; ISO:RGD. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:RGD. DR GO; GO:0030182; P:neuron differentiation; IEP:RGD. DR GO; GO:1900039; P:positive regulation of cellular response to hypoxia; IMP:RGD. DR GO; GO:0043045; P:post-fertilization epigenetic regulation of gene expression; ISO:RGD. DR GO; GO:0042220; P:response to cocaine; IEP:RGD. DR GO; GO:0032355; P:response to estradiol; IEP:RGD. DR GO; GO:0045471; P:response to ethanol; IEP:RGD. DR GO; GO:0010212; P:response to ionizing radiation; IEP:RGD. DR GO; GO:0010288; P:response to lead ion; IEP:RGD. DR GO; GO:0031667; P:response to nutrient levels; IEP:RGD. DR GO; GO:0009636; P:response to toxic substance; IEP:RGD. DR GO; GO:0033189; P:response to vitamin A; IEP:RGD. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEP:RGD. DR GO; GO:0007283; P:spermatogenesis; ISO:RGD. 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 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; Q1LZ53; RN. PE 1: Evidence at protein level; KW Alternative promoter usage; Chromatin regulator; Chromosome; Cytoplasm; KW 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_0000313030" FT DOMAIN 257..315 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:0000250" FT COMPBIAS 12..41 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 63..82 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:22673903" FT MOD_RES 120 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:22673903" FT MOD_RES 167 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0000250|UniProtKB:O88508" FT MOD_RES 239 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:22673903" FT MOD_RES 251 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:22673903" FT MOD_RES 257 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q9Y6K1" FT MOD_RES 386 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O88508" FT MOD_RES 389 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O88508" FT MOD_RES 706 FT /note="S-methylcysteine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:O88508" 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:15203217" FT /id="VSP_029986" SQ SEQUENCE 908 AA; 101669 MW; 6CCE9EB4E9CEB409 CRC64; MPSSGPGDTS ISSLEREDDR KEGEEQEENR GKEERQEPSA TARKVGRPGR KRKHPPVESS DTPKDPAVTT KSQPTAQDSG PSDLLPNGDL EKRSEPQPEE GSPAAGQKGG APAEGEGTET PPEASRAVEN GCCVTKEGRG ASAGEGKEQK QTNIESMKME GSRGRLRGGL GWESSLRQRP MPRLTFQAGD PYYISKRKRD EWLARWKREA EKKAKVIAVM NAVEESQASG ESQKVEEASP PAVQQPTDPA SPTVATTPEP VGADAGDKNA TKAADDEPEY EDGRGFGIGE LVWGKLRGFS WWPGRIVSWW MTGRSRAAEG TRWVMWFGDG KFSVVCVEKL MPLSSFCSAF HQATYNKQPM YRKAIYEVLQ VASSRAGKLF PACHDSDESD TGKAVEVQNK 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 //