DNM3L_HUMAN
ID DNM3L_HUMAN Reviewed; 386 AA.
AC Q9UJW3; E9PB42; Q9BUJ4;
DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot.
DT 31-MAY-2011, sequence version 3.
DT 03-AUG-2022, entry version 178.
DE RecName: Full=DNA (cytosine-5)-methyltransferase 3-like;
GN Name=DNMT3L;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), ALTERNATIVE SPLICING, AND TISSUE
RP SPECIFICITY.
RX PubMed=10857753; DOI=10.1006/geno.2000.6168;
RA Aapola U., Shibuya K., Scott H.S., Ollila J., Vihinen M., Heino M.,
RA Shintani A., Kawasaki K., Minoshima S., Krohn K., Antonarakis S.E.,
RA Shimizu N., Kudoh J., Peterson P.;
RT "Isolation and initial characterization of a novel zinc finger gene,
RT DNMT3L, on 21q22.3, related to the cytosine-5-methyltransferase 3 gene
RT family.";
RL Genomics 65:293-298(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10830953; DOI=10.1038/35012518;
RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T., Park H.-S.,
RA Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y., Soeda E., Ohki M.,
RA Takagi T., Sakaki Y., Taudien S., Blechschmidt K., Polley A., Menzel U.,
RA Delabar J., Kumpf K., Lehmann R., Patterson D., Reichwald K., Rump A.,
RA Schillhabel M., Schudy A., Zimmermann W., Rosenthal A., Kudoh J.,
RA Shibuya K., Kawasaki K., Asakawa S., Shintani A., Sasaki T., Nagamine K.,
RA Mitsuyama S., Antonarakis S.E., Minoshima S., Shimizu N., Nordsiek G.,
RA Hornischer K., Brandt P., Scharfe M., Schoen O., Desario A., Reichelt J.,
RA Kauer G., Bloecker H., Ramser J., Beck A., Klages S., Hennig S.,
RA Riesselmann L., Dagand E., Wehrmeyer S., Borzym K., Gardiner K.,
RA Nizetic D., Francis F., Lehrach H., Reinhardt R., Yaspo M.-L.;
RT "The DNA sequence of human chromosome 21.";
RL Nature 405:311-319(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT GLY-278.
RC TISSUE=Placenta;
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 [5]
RP X-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS), FUNCTION, AND HOMODIMERIZATION.
RX PubMed=17687327; DOI=10.1038/nature05987;
RA Ooi S.K., Qiu C., Bernstein E., Li K., Jia D., Yang Z.,
RA Erdjument-Bromage H., Tempst P., Lin S.-P., Allis C.D., Cheng X.,
RA Bestor T.H.;
RT "DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation
RT of DNA.";
RL Nature 448:714-717(2007).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (2.89 ANGSTROMS) OF 160-387, SUBUNIT, AND MUTAGENESIS
RP OF PHE-261.
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).
CC -!- FUNCTION: Catalytically inactive regulatory factor of DNA
CC methyltransferases that can either promote or inhibit DNA methylation
CC depending on the context (By similarity). Essential for the function of
CC DNMT3A and DNMT3B: activates DNMT3A and DNMT3B by binding to their
CC catalytic domain (PubMed:17687327). Acts by accelerating the binding of
CC DNA and S-adenosyl-L-methionine (AdoMet) to the methyltransferases and
CC dissociates from the complex after DNA binding to the
CC methyltransferases (PubMed:17687327). Recognizes unmethylated histone
CC H3 lysine 4 (H3K4me0) and induces de novo DNA methylation by
CC recruitment or activation of DNMT3 (PubMed:17687327). Plays a key role
CC in embryonic stem cells and germ cells (By similarity). In germ cells,
CC required for the methylation of imprinted loci together with DNMT3A (By
CC similarity). In male germ cells, specifically required to methylate
CC retrotransposons, preventing their mobilization (By similarity). Plays
CC a key role in embryonic stem cells (ESCs) by acting both as an positive
CC and negative regulator of DNA methylation (By similarity). While it
CC promotes DNA methylation of housekeeping genes together with DNMT3A and
CC DNMT3B, it also acts as an inhibitor of DNA methylation at the promoter
CC of bivalent genes (By similarity). Interacts with the EZH2 component of
CC the PRC2/EED-EZH2 complex, preventing interaction of DNMT3A and DNMT3B
CC with the PRC2/EED-EZH2 complex, leading to maintain low methylation
CC levels at the promoters of bivalent genes (By similarity). Promotes
CC differentiation of ESCs into primordial germ cells by inhibiting DNA
CC methylation at the promoter of RHOX5, thereby activating its expression
CC (By similarity). {ECO:0000250|UniProtKB:Q9CWR8,
CC ECO:0000269|PubMed:17687327}.
CC -!- SUBUNIT: Homodimer (PubMed:17687327, PubMed:17713477). Heterotetramer
CC composed of 1 DNMT3A homodimer and 2 DNMT3L subunits (DNMT3L-DNMT3A-
CC DNMT3A-DNMT3L) (PubMed:17713477). Interacts with histone H3 (via N-
CC terminus); interaction is strongly inhibited by methylation at lysine 4
CC (H3K4me) (PubMed:17687327). Interacts with EZH2; the interaction is
CC direct (By similarity). Interacts with SPOCD1 (By similarity).
CC {ECO:0000250|UniProtKB:Q9CWR8, ECO:0000269|PubMed:17687327,
CC ECO:0000269|PubMed:17713477}.
CC -!- INTERACTION:
CC Q9UJW3; Q13547: HDAC1; NbExp=3; IntAct=EBI-740967, EBI-301834;
CC Q9UJW3; Q17RL8: PDZD4; NbExp=3; IntAct=EBI-740967, EBI-10239064;
CC Q9UJW3; Q9UHA3: RSL24D1; NbExp=7; IntAct=EBI-740967, EBI-749321;
CC Q9UJW3-1; Q9Y6K1: DNMT3A; NbExp=5; IntAct=EBI-15650345, EBI-923653;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000305}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Comment=Other splice isoforms seem to exist.;
CC Name=1;
CC IsoId=Q9UJW3-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9UJW3-2; Sequence=VSP_041295;
CC -!- TISSUE SPECIFICITY: Expressed at low levels in several tissues
CC including testis, ovary, and thymus. {ECO:0000269|PubMed:10857753}.
CC -!- MISCELLANEOUS: Interaction with histone H3 is strongly inhibited by
CC methylation at lysine 4 (H3K4me).
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DR EMBL; AF194032; AAF05812.1; -; mRNA.
DR EMBL; AP001753; BAA95556.1; -; Genomic_DNA.
DR EMBL; AP001059; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP001060; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471079; EAX09445.1; -; Genomic_DNA.
DR EMBL; BC002560; AAH02560.1; -; mRNA.
DR CCDS; CCDS13705.1; -. [Q9UJW3-2]
DR CCDS; CCDS46650.1; -. [Q9UJW3-1]
DR RefSeq; NP_037501.2; NM_013369.3. [Q9UJW3-2]
DR RefSeq; NP_787063.1; NM_175867.2. [Q9UJW3-1]
DR PDB; 2PV0; X-ray; 3.30 A; A/B/C=1-386.
DR PDB; 2PVC; X-ray; 3.69 A; A/B/C=1-386.
DR PDB; 2QRV; X-ray; 2.89 A; B/C/F/G=160-386.
DR PDB; 4U7P; X-ray; 3.82 A; B=178-379.
DR PDB; 4U7T; X-ray; 2.90 A; B/D=178-379.
DR PDB; 5YX2; X-ray; 2.65 A; B/C=178-385.
DR PDB; 6BRR; X-ray; 2.97 A; B/C=178-386.
DR PDB; 6F57; X-ray; 3.10 A; B/C=178-386.
DR PDB; 6KDA; X-ray; 2.91 A; B/C=178-379.
DR PDB; 6KDB; X-ray; 2.86 A; B/C=178-379.
DR PDB; 6KDL; X-ray; 3.27 A; B/C=178-379.
DR PDB; 6KDP; X-ray; 2.93 A; B/C=178-379.
DR PDB; 6KDT; X-ray; 2.87 A; B/C=178-379.
DR PDB; 6U8P; X-ray; 3.05 A; B/C=178-386.
DR PDB; 6U8V; X-ray; 3.00 A; B/C=178-386.
DR PDB; 6U8W; X-ray; 2.95 A; B/C=178-386.
DR PDB; 6U8X; X-ray; 2.95 A; B/C=178-386.
DR PDB; 6U90; X-ray; 3.00 A; B/C=178-386.
DR PDB; 6U91; X-ray; 3.00 A; B/C=178-386.
DR PDB; 6W89; X-ray; 2.50 A; B/C/H/I=178-386.
DR PDB; 6W8B; X-ray; 2.40 A; B/C/I/J=178-386.
DR PDB; 6W8D; X-ray; 2.60 A; B/C=178-386.
DR PDB; 6W8J; X-ray; 2.44 A; B/C=178-386.
DR PDBsum; 2PV0; -.
DR PDBsum; 2PVC; -.
DR PDBsum; 2QRV; -.
DR PDBsum; 4U7P; -.
DR PDBsum; 4U7T; -.
DR PDBsum; 5YX2; -.
DR PDBsum; 6BRR; -.
DR PDBsum; 6F57; -.
DR PDBsum; 6KDA; -.
DR PDBsum; 6KDB; -.
DR PDBsum; 6KDL; -.
DR PDBsum; 6KDP; -.
DR PDBsum; 6KDT; -.
DR PDBsum; 6U8P; -.
DR PDBsum; 6U8V; -.
DR PDBsum; 6U8W; -.
DR PDBsum; 6U8X; -.
DR PDBsum; 6U90; -.
DR PDBsum; 6U91; -.
DR PDBsum; 6W89; -.
DR PDBsum; 6W8B; -.
DR PDBsum; 6W8D; -.
DR PDBsum; 6W8J; -.
DR AlphaFoldDB; Q9UJW3; -.
DR SMR; Q9UJW3; -.
DR BioGRID; 118984; 82.
DR ComplexPortal; CPX-6276; DNA (cytosine-5)-methyltransferase 3B complex.
DR ComplexPortal; CPX-944; DNA (cytosine-5)-methyltransferase 3A complex.
DR CORUM; Q9UJW3; -.
DR DIP; DIP-35238N; -.
DR IntAct; Q9UJW3; 9.
DR MINT; Q9UJW3; -.
DR STRING; 9606.ENSP00000270172; -.
DR BindingDB; Q9UJW3; -.
DR ChEMBL; CHEMBL3137291; -.
DR ChEMBL; CHEMBL3885560; -.
DR REBASE; 4636; M.HsaDnmt3L.
DR iPTMnet; Q9UJW3; -.
DR PhosphoSitePlus; Q9UJW3; -.
DR BioMuta; DNMT3L; -.
DR DMDM; 334302913; -.
DR PaxDb; Q9UJW3; -.
DR PeptideAtlas; Q9UJW3; -.
DR PRIDE; Q9UJW3; -.
DR ABCD; Q9UJW3; 1 sequenced antibody.
DR Antibodypedia; 10145; 594 antibodies from 41 providers.
DR DNASU; 29947; -.
DR Ensembl; ENST00000270172.7; ENSP00000270172.3; ENSG00000142182.9. [Q9UJW3-2]
DR Ensembl; ENST00000628202.3; ENSP00000486001.1; ENSG00000142182.9. [Q9UJW3-1]
DR GeneID; 29947; -.
DR KEGG; hsa:29947; -.
DR MANE-Select; ENST00000628202.3; ENSP00000486001.1; NM_175867.3; NP_787063.1.
DR UCSC; uc002zeg.3; human. [Q9UJW3-1]
DR CTD; 29947; -.
DR DisGeNET; 29947; -.
DR GeneCards; DNMT3L; -.
DR HGNC; HGNC:2980; DNMT3L.
DR HPA; ENSG00000142182; Tissue enhanced (liver).
DR MIM; 606588; gene.
DR neXtProt; NX_Q9UJW3; -.
DR OpenTargets; ENSG00000142182; -.
DR PharmGKB; PA27447; -.
DR VEuPathDB; HostDB:ENSG00000142182; -.
DR eggNOG; ENOG502SIGQ; Eukaryota.
DR GeneTree; ENSGT00940000162228; -.
DR InParanoid; Q9UJW3; -.
DR OMA; EDVCICC; -.
DR OrthoDB; 1015783at2759; -.
DR TreeFam; TF329039; -.
DR PathwayCommons; Q9UJW3; -.
DR Reactome; R-HSA-5334118; DNA methylation.
DR SignaLink; Q9UJW3; -.
DR BioGRID-ORCS; 29947; 6 hits in 1072 CRISPR screens.
DR EvolutionaryTrace; Q9UJW3; -.
DR GeneWiki; DNMT3L; -.
DR GenomeRNAi; 29947; -.
DR Pharos; Q9UJW3; Tbio.
DR PRO; PR:Q9UJW3; -.
DR Proteomes; UP000005640; Chromosome 21.
DR RNAct; Q9UJW3; protein.
DR Bgee; ENSG00000142182; Expressed in liver and 57 other tissues.
DR ExpressionAtlas; Q9UJW3; baseline and differential.
DR Genevisible; Q9UJW3; HS.
DR GO; GO:1902494; C:catalytic complex; IPI:ComplexPortal.
DR GO; GO:0000794; C:condensed nuclear chromosome; IEA:Ensembl.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; HDA:UniProtKB.
DR GO; GO:0035098; C:ESC/E(Z) complex; IEA:Ensembl.
DR GO; GO:0000792; C:heterochromatin; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; HDA:UniProtKB.
DR GO; GO:0008047; F:enzyme activator activity; IDA:MGI.
DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0090116; P:C-5 methylation of cytosine; IDA:ComplexPortal.
DR GO; GO:0060718; P:chorionic trophoblast cell differentiation; IEA:Ensembl.
DR GO; GO:0006306; P:DNA methylation; NAS:UniProtKB.
DR GO; GO:0043046; P:DNA methylation involved in gamete generation; ISS:UniProtKB.
DR GO; GO:0032776; P:DNA methylation on cytosine; ISS:UniProtKB.
DR GO; GO:0071514; P:genomic imprinting; IEA:Ensembl.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0007141; P:male meiosis I; ISS:UniProtKB.
DR GO; GO:1905642; P:negative regulation of DNA methylation; ISS:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0010529; P:negative regulation of transposition; IEA:Ensembl.
DR GO; GO:0001890; P:placenta development; IEA:Ensembl.
DR GO; GO:1905643; P:positive regulation of DNA methylation; ISS:UniProtKB.
DR GO; GO:0006349; P:regulation of gene expression by genomic imprinting; NAS:UniProtKB.
DR GO; GO:0007283; P:spermatogenesis; ISS:UniProtKB.
DR GO; GO:0048863; P:stem cell differentiation; ISS:UniProtKB.
DR Gene3D; 3.30.40.10; -; 1.
DR Gene3D; 3.40.50.150; -; 1.
DR InterPro; IPR025766; ADD.
DR InterPro; IPR040552; DNMT3_ADD.
DR InterPro; IPR030486; DNMT3L.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR011011; Znf_FYVE_PHD.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR PANTHER; PTHR23068:SF13; PTHR23068:SF13; 1.
DR Pfam; PF17980; ADD_DNMT3; 1.
DR SUPFAM; SSF57903; SSF57903; 1.
DR PROSITE; PS51533; ADD; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Differentiation; Metal-binding;
KW Nucleus; Reference proteome; Spermatogenesis; Zinc; Zinc-finger.
FT CHAIN 1..386
FT /note="DNA (cytosine-5)-methyltransferase 3-like"
FT /id="PRO_0000088047"
FT DOMAIN 41..173
FT /note="ADD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00865"
FT ZN_FING 52..82
FT /note="GATA-type; atypical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00865"
FT ZN_FING 93..149
FT /note="PHD-type; atypical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00865"
FT VAR_SEQ 332
FT /note="S -> SS (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:10857753"
FT /id="VSP_041295"
FT VARIANT 278
FT /note="R -> G (in dbSNP:rs7354779)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_051962"
FT MUTAGEN 261
FT /note="F->A: Loss of binding to DNMT3A."
FT /evidence="ECO:0000269|PubMed:17713477"
FT CONFLICT 246
FT /note="P -> A (in Ref. 1; AAF05812)"
FT /evidence="ECO:0000305"
FT CONFLICT 266
FT /note="L -> F (in Ref. 1; AAF05812)"
FT /evidence="ECO:0000305"
FT HELIX 35..43
FT /evidence="ECO:0007829|PDB:2PV0"
FT HELIX 49..51
FT /evidence="ECO:0007829|PDB:2PV0"
FT TURN 54..56
FT /evidence="ECO:0007829|PDB:2PV0"
FT STRAND 66..71
FT /evidence="ECO:0007829|PDB:2PV0"
FT HELIX 74..81
FT /evidence="ECO:0007829|PDB:2PV0"
FT TURN 82..85
FT /evidence="ECO:0007829|PDB:2PV0"
FT STRAND 89..93
FT /evidence="ECO:0007829|PDB:2PV0"
FT TURN 97..99
FT /evidence="ECO:0007829|PDB:2PV0"
FT HELIX 119..125
FT /evidence="ECO:0007829|PDB:2PV0"
FT HELIX 130..136
FT /evidence="ECO:0007829|PDB:2PV0"
FT TURN 143..145
FT /evidence="ECO:0007829|PDB:2PV0"
FT STRAND 154..156
FT /evidence="ECO:0007829|PDB:2PV0"
FT HELIX 160..171
FT /evidence="ECO:0007829|PDB:2PV0"
FT HELIX 184..186
FT /evidence="ECO:0007829|PDB:6W8B"
FT STRAND 192..197
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 200..204
FT /evidence="ECO:0007829|PDB:6W8B"
FT TURN 205..207
FT /evidence="ECO:0007829|PDB:6W8B"
FT STRAND 218..222
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 224..226
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 229..234
FT /evidence="ECO:0007829|PDB:6W8B"
FT STRAND 239..244
FT /evidence="ECO:0007829|PDB:6W8B"
FT STRAND 248..250
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 256..269
FT /evidence="ECO:0007829|PDB:6W8B"
FT STRAND 281..286
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 292..301
FT /evidence="ECO:0007829|PDB:6W8B"
FT STRAND 307..310
FT /evidence="ECO:0007829|PDB:6W8B"
FT STRAND 314..316
FT /evidence="ECO:0007829|PDB:2PV0"
FT STRAND 320..325
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 329..332
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 340..353
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 361..366
FT /evidence="ECO:0007829|PDB:6W8B"
FT HELIX 367..371
FT /evidence="ECO:0007829|PDB:6W8B"
FT TURN 372..374
FT /evidence="ECO:0007829|PDB:6W8B"
SQ SEQUENCE 386 AA; 43583 MW; 65EC2AB7492D53B3 CRC64;
MAAIPALDPE AEPSMDVILV GSSELSSSVS PGTGRDLIAY EVKANQRNIE DICICCGSLQ
VHTQHPLFEG GICAPCKDKF LDALFLYDDD GYQSYCSICC SGETLLICGN PDCTRCYCFE
CVDSLVGPGT SGKVHAMSNW VCYLCLPSSR SGLLQRRRKW RSQLKAFYDR ESENPLEMFE
TVPVWRRQPV RVLSLFEDIK KELTSLGFLE SGSDPGQLKH VVDVTDTVRK DVEEWGPFDL
VYGATPPLGH TCDRPPSWYL FQFHRLLQYA RPKPGSPRPF FWMFVDNLVL NKEDLDVASR
FLEMEPVTIP DVHGGSLQNA VRVWSNIPAI RSRHWALVSE EELSLLAQNK QSSKLAAKWP
TKLVKNCFLP LREYFKYFST ELTSSL
