DNM3A_RAT
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 03-AUG-2022, entry version 120.
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}.
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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; Q1LZ53; -.
DR PRIDE; Q1LZ53; -.
DR Ensembl; ENSRNOT00000047210; ENSRNOP00000046524; ENSRNOG00000026649. [Q1LZ53-1]
DR GeneID; 444984; -.
DR KEGG; rno:444984; -.
DR CTD; 1788; -.
DR RGD; 1303336; Dnmt3a.
DR eggNOG; ENOG502QR6U; Eukaryota.
DR GeneTree; ENSGT00940000155459; -.
DR InParanoid; Q1LZ53; -.
DR OMA; DGKFSVX; -.
DR OrthoDB; 1015783at2759; -.
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 tissues.
DR Genevisible; Q1LZ53; RN.
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; IDA:RGD.
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:0007568; P:aging; IEP: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:0043045; P:DNA methylation involved in embryo development; ISO:RGD.
DR GO; GO:0043046; P:DNA methylation involved in gamete generation; ISO:RGD.
DR GO; GO:0032776; P:DNA methylation on cytosine; IDA:RGD.
DR GO; GO:0006346; P:DNA methylation-dependent heterochromatin assembly; ISO:RGD.
DR GO; GO:0097284; P:hepatocyte apoptotic process; IEP:RGD.
DR GO; GO:0044027; P:hypermethylation of CpG island; ISO:RGD.
DR GO; GO:0000278; P:mitotic cell cycle; IEP:RGD.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IBA:GO_Central.
DR GO; GO:0030182; P:neuron differentiation; IEP:RGD.
DR GO; GO:0010942; P:positive regulation of cell death; IMP:RGD.
DR GO; GO:0006349; P:regulation of gene expression by genomic imprinting; 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 Gene3D; 3.40.50.150; -; 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.
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 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
