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Protein

Histone-lysine N-methyltransferase SETDB1

Gene

Setdb1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Histone methyltransferase that specifically trimethylates 'Lys-9' of histone H3. H3 'Lys-9' trimethylation represents a specific tag for epigenetic transcriptional repression by recruiting HP1 (CBX1, CBX3 and/or CBX5) proteins to methylated histones. Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes. H3 'Lys-9' trimethylation is coordinated with DNA methylation. Probably forms a complex with MBD1 and ATF7IP that represses transcription and couples DNA methylation and histone 'Lys-9' trimethylation. Its activity is dependent on MBD1 and is heritably maintained through DNA replication by being recruited by CAF-1. SETDB1 is targeted to histone H3 by TRIM28/TIF1B, a factor recruited by KRAB zinc-finger proteins. Probably forms a corepressor complex required for activated KRAS-mediated promoter hypermethylation and transcriptional silencing of tumor suppressor genes (TSGs) or other tumor-related genes in colorectal cancer (CRC) cells (By similarity). Also required to maintain a transcriptionally repressive state of genes in undifferentiated embryonic stem cells (ESCs) (By similarity). Associates at promoter regions of tumor suppressor genes (TSGs) leading to their gene silencing. The SETDB1-TRIM28-ZNF274 complex may play a role in recruiting ATRX to the 3'-exons of zinc-finger coding genes with atypical chromatin signatures to establish or maintain/protect H3K9me3 at these transcriptionally active regions (By similarity).By similarity

Catalytic activityi

S-adenosyl-L-methionine + L-lysine-[histone] = S-adenosyl-L-homocysteine + N(6)-methyl-L-lysine-[histone].PROSITE-ProRule annotation1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi746Zinc 1By similarity1
Metal bindingi746Zinc 2By similarity1
Metal bindingi748Zinc 1By similarity1
Metal bindingi752Zinc 1By similarity1
Metal bindingi752Zinc 3By similarity1
Metal bindingi758Zinc 1By similarity1
Metal bindingi760Zinc 2By similarity1
Metal bindingi798Zinc 2By similarity1
Metal bindingi798Zinc 3By similarity1
Metal bindingi802Zinc 2By similarity1
Metal bindingi804Zinc 3By similarity1
Metal bindingi809Zinc 3By similarity1
Binding sitei868S-adenosyl-L-methioninePROSITE-ProRule annotation1
Binding sitei870S-adenosyl-L-methioninePROSITE-ProRule annotation1
Binding sitei1236S-adenosyl-L-methioninePROSITE-ProRule annotation1
Metal bindingi1242Zinc 4By similarity1
Metal bindingi1295Zinc 4By similarity1
Metal bindingi1297Zinc 4By similarity1
Metal bindingi1302Zinc 4By similarity1

GO - Molecular functioni

GO - Biological processi

  • bone development Source: MGI
  • histone H3-K9 trimethylation Source: MGI
  • inner cell mass cell proliferation Source: MGI
  • negative regulation of transcription from RNA polymerase II promoter Source: MGI
  • positive regulation of methylation-dependent chromatin silencing Source: UniProtKB
  • Ras protein signal transduction Source: UniProtKB
  • transcription, DNA-templated Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Chromatin regulator, Methyltransferase, Repressor, Transferase

Keywords - Biological processi

Transcription, Transcription regulation

Keywords - Ligandi

Metal-binding, S-adenosyl-L-methionine, Zinc

Names & Taxonomyi

Protein namesi
Recommended name:
Histone-lysine N-methyltransferase SETDB1 (EC:2.1.1.43)
Alternative name(s):
ERG-associated protein with SET domain
Short name:
ESET
SET domain bifurcated 1
Gene namesi
Name:Setdb1
Synonyms:Eset, Kiaa0067
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Unplaced

Organism-specific databases

MGIiMGI:1934229. Setdb1.

Subcellular locationi

  • Nucleus By similarity
  • Chromosome By similarity

  • Note: Associated with non-pericentromeric regions of chromatin.By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Chromosome, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi798C → T: Abolishes methyltransferase activity. 1 Publication1
Mutagenesisi1242C → T: Abolishes methyltransferase activity. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001860651 – 1307Histone-lysine N-methyltransferase SETDB1Add BLAST1307

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei112PhosphoserineCombined sources1
Modified residuei117PhosphoserineCombined sources1
Modified residuei120PhosphothreonineCombined sources1
Cross-linki182Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei993Phosphothreonine; by NLKBy similarity1
Modified residuei1042PhosphoserineBy similarity1
Cross-linki1049Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1)By similarity
Cross-linki1049Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)By similarity
Cross-linki1085Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)By similarity
Modified residuei1186N6,N6,N6-trimethyllysine; alternateBy similarity1
Modified residuei1186N6,N6-dimethyllysine; alternateBy similarity1
Modified residuei1194N6,N6,N6-trimethyllysine; alternateBy similarity1
Modified residuei1194N6,N6-dimethyllysine; alternateBy similarity1

Keywords - PTMi

Isopeptide bond, Methylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiO88974.
MaxQBiO88974.
PaxDbiO88974.
PeptideAtlasiO88974.
PRIDEiO88974.

PTM databases

iPTMnetiO88974.
PhosphoSitePlusiO88974.

Expressioni

Tissue specificityi

Ubiquitously expressed. Strong expression in liver and testis.1 Publication

Gene expression databases

CleanExiMM_SETDB1.

Interactioni

Subunit structurei

Part of a complex containing at least CDYL, REST, WIZ, SETB1, EHMT1 and EHMT2. During DNA replication, it is recruited by SETDB1 to form a S phase-specific complex that facilitates methylation of H3 'Lys-9' during replication-coupled chromatin assembly and is at least composed of the CAF-1 subunit CHAF1A, MBD1 and SETDB1. Probably part of a corepressor complex containing ZNF304, TRIM28, SETDB1 and DNMT1. Interacts with TRIM28/TIF1B. Interacts with ATF7IP and ATF7IP2; the interaction with ATF7IP is required to stimulate histone methyltransferase activity and facilitate the conversion of dimethylated to trimethylated H3 'Lys-9'. Interacts with MBD1; interaction is abolished when MBD1 is sumoylated. Interacts with CBX1 and CBX5. Interacts with DNMT3A and DNMT3B. Interacts with SUMO2. Interacts with CHD7, NLK1 and PPARG. Interacts with MPHOSPH8 (By similarity). Interacts with ERG (PubMed:11791185). Interacts with HDAC1, HDAC2, SIN3A, SIN3B (PubMed:12398767). Interacts with ATRX. Forms a complex with ATRX, TRIM28 and ZNF274 (By similarity).By similarity2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
ErgP812703EBI-79658,EBI-79647

Protein-protein interaction databases

IntActiO88974. 9 interactors.
MINTiMINT-1753431.
STRINGi10090.ENSMUSP00000015841.

Structurei

3D structure databases

ProteinModelPortaliO88974.
SMRiO88974.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini257 – 320Tudor 1Add BLAST64
Domaini347 – 403Tudor 2Add BLAST57
Domaini611 – 682MBDPROSITE-ProRule annotationAdd BLAST72
Domaini744 – 817Pre-SETPROSITE-ProRule annotationAdd BLAST74
Domaini820 – 1282SETPROSITE-ProRule annotationAdd BLAST463
Domaini1291 – 1307Post-SETPROSITE-ProRule annotationAdd BLAST17

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni830 – 832S-adenosyl-L-methionine bindingBy similarity3
Regioni1239 – 1240S-adenosyl-L-methionine bindingBy similarity2

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili30 – 65Sequence analysisAdd BLAST36

Domaini

The pre-SET, SET and post-SET domains are all required for methyltransferase activity. The 347-amino-acid insertion in the SET domain has no effect on the catalytic activity.
In the pre-SET domain, Cys residues bind 3 zinc ions that are arranged in a triangular cluster; some of these Cys residues contribute to the binding of two zinc ions within the cluster.By similarity

Sequence similaritiesi

Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. Suvar3-9 subfamily.PROSITE-ProRule annotation
Contains 1 MBD (methyl-CpG-binding) domain.PROSITE-ProRule annotation
Contains 1 post-SET domain.PROSITE-ProRule annotation
Contains 1 pre-SET domain.PROSITE-ProRule annotation
Contains 1 SET domain.PROSITE-ProRule annotation
Contains 2 Tudor domains.Curated

Keywords - Domaini

Coiled coil, Repeat

Phylogenomic databases

eggNOGiKOG1141. Eukaryota.
COG2940. LUCA.
HOVERGENiHBG061013.
InParanoidiO88974.

Family and domain databases

InterProiIPR016177. DNA-bd_dom.
IPR025796. Hist-Lys_N-MeTrfase_SETDB1.
IPR001739. Methyl_CpG_DNA-bd.
IPR003616. Post-SET_dom.
IPR007728. Pre-SET_dom.
IPR001214. SET_dom.
IPR002999. Tudor.
[Graphical view]
PfamiPF01429. MBD. 1 hit.
PF05033. Pre-SET. 1 hit.
PF00856. SET. 1 hit.
[Graphical view]
SMARTiSM00391. MBD. 1 hit.
SM00468. PreSET. 1 hit.
SM00317. SET. 1 hit.
SM00333. TUDOR. 2 hits.
[Graphical view]
SUPFAMiSSF54171. SSF54171. 1 hit.
PROSITEiPS50982. MBD. 1 hit.
PS50868. POST_SET. 1 hit.
PS50867. PRE_SET. 1 hit.
PS51573. SAM_MT43_SUVAR39_1. 1 hit.
PS50280. SET. 1 hit.
[Graphical view]

Sequences (7)i

Sequence statusi: Complete.

This entry describes 7 isoformsi produced by alternative splicing. AlignAdd to basket

Note: Experimental confirmation may be lacking for some isoforms.
Isoform 1 (identifier: O88974-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MSSLPGCMSL AAAPAAADSA EIAELQQAVV EELGISMEEL RQYIDEELEK
60 70 80 90 100
MDCIQQRKKQ LAELETWVLQ KESEVAYVDR LFDDASREVT NCESLVKDFY
110 120 130 140 150
SKLGLQYHDS SSEDEASRPT EIIEIPDEDD DVLSIDSGDA GSRTPKDQKL
160 170 180 190 200
REAMAALRKS AQDVQKFMDA VNKKSSSQDL HKGTLGQVSG ELSKDGDLIV
210 220 230 240 250
SMRILGKKRT KTWHKGTLIA IQTVGLGKKY KVKFDNKGKS LLSGNHIAYD
260 270 280 290 300
YHPPADKLFV GSRVVAKYKD GNQVWLYAGI VAETPNVKNK LRFLIFFDDG
310 320 330 340 350
YASYVTQSEL YPICRPLKKT WEDIEDSSCR DFIEEYITAY PNRPMVLLKS
360 370 380 390 400
GQLIKTEWEG TWWKSRVEEV DGSLVRILFL DDKRCEWIYR GSTRLEPMFS
410 420 430 440 450
MKTSSASAME KKQGGQLRTR PNMGAVRSKG PVVQYTQDLT GTGIQFKPME
460 470 480 490 500
PLQPIAPPAP LPIPPLSPQA ADTDLESQLA QSRKQVAKKS TSFRPGSVGS
510 520 530 540 550
GHSSPTSSTL SENVSAGKLG INQTYRSPLA SVTSTPASAA PPVPPVPPGP
560 570 580 590 600
PTPPGPPAPP GPLAPPAFHG MLERAPAEPS YRAPMEKLFY LPHVCSYTCL
610 620 630 640 650
SRIRPMRNEQ YRGKNPLLVP LLYDFRRMTA RRRVNRKMGF HVIYKTPCGL
660 670 680 690 700
CLRTMQEIER YLFETGCDFL FLEMFCLDPY VLVDRKFQPF KPFYYILDIT
710 720 730 740 750
YGKEDVPLSC VNEIDTTPPP QVAYSKERIP GKGVFINTGP EFLVGCDCKD
760 770 780 790 800
GCRDKSKCAC HQLTIQATAC TPGGQVNPNS GYQYKRLEEC LPTGVYECNK
810 820 830 840 850
RCNCDPNMCT NRLVQHGLQV RLQLFKTQNK GWGIRCLDDI AKGSFVCIYA
860 870 880 890 900
GKILTDDFAD KEGLEMGDEY FANLDHIESV ENFKEGYESD VPTSSDSSGV
910 920 930 940 950
DMKDQEDGNS GSEDPEESND DSSDDNFCKD EDFSTSSVWR SYATRRQTRG
960 970 980 990 1000
QKENELSEMT SKDSRPPDLG PPHVPIPSSV SVGGCNPPSS EETPKNKVAS
1010 1020 1030 1040 1050
WLSCNSVSEG GFADSDSRSS FKTSEGGDGR AGGGRGEAER ASTSGLSFKD
1060 1070 1080 1090 1100
EGDNKQPKKE DPENRNKMPV VTEGSQNHGH NPPMKSEGLR RPASKMSVLQ
1110 1120 1130 1140 1150
SQRVVTSTQS NPDDILTLSS STESEGESGT SRKPTAGHTS ATAVDSDDIQ
1160 1170 1180 1190 1200
TISSGSDGDD FEDKKNLSGP TKRQVAVKST RGFALKSTHG IAIKSTNMAS
1210 1220 1230 1240 1250
VDKGESAPVR KNTRQFYDGE ESCYIIDAKL EGNLGRYLNH SCSPNLFVQN
1260 1270 1280 1290 1300
VFVDTHDLRF PWVAFFASKR IRAGTELTWD YNYEVGSVEG KELLCCCGAI

ECRGRLL
Length:1,307
Mass (Da):144,549
Last modified:November 1, 1998 - v1
Checksum:i326AED6371D156C2
GO
Isoform 2 (identifier: O88974-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     482-486: SRKQV → AQSQK
     489-1307: Missing.

Show »
Length:488
Mass (Da):54,696
Checksum:i8874BF6A963B5415
GO
Isoform 3 (identifier: O88974-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-807: Missing.

Show »
Length:500
Mass (Da):54,477
Checksum:i164B400024020B2F
GO
Isoform 4 (identifier: O88974-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     474-474: D → ES

Show »
Length:1,308
Mass (Da):144,650
Checksum:iE224818F50D56E25
GO
Isoform 5 (identifier: O88974-5) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     527-1307: Missing.

Show »
Length:526
Mass (Da):58,617
Checksum:iF5B6903C06D91D11
GO
Isoform 6 (identifier: O88974-6) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     474-474: D → ES
     527-1307: Missing.

Show »
Length:527
Mass (Da):58,719
Checksum:iF2B3561EAA10EC06
GO
Isoform 7 (identifier: O88974-7) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     756-1307: Missing.

Note: No experimental confirmation available.
Show »
Length:755
Mass (Da):84,400
Checksum:i3AE0FFE5C3542A60
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti463I → M in BAC40439 (PubMed:16141072).Curated1
Sequence conflicti1092P → S in BAC65480 (PubMed:12693553).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0022211 – 807Missing in isoform 3. 1 PublicationAdd BLAST807
Alternative sequenceiVSP_024031474D → ES in isoform 4 and isoform 6. 2 Publications1
Alternative sequenceiVSP_002219482 – 486SRKQV → AQSQK in isoform 2. 1 Publication5
Alternative sequenceiVSP_002220489 – 1307Missing in isoform 2. 1 PublicationAdd BLAST819
Alternative sequenceiVSP_024032527 – 1307Missing in isoform 5 and isoform 6. 1 PublicationAdd BLAST781
Alternative sequenceiVSP_024033756 – 1307Missing in isoform 7. 1 PublicationAdd BLAST552

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF091628 mRNA. Translation: AAC43039.1.
AY091600 mRNA. Translation: AAM13922.1.
AF546078 mRNA. Translation: AAN52358.1.
AY226577 Genomic DNA. Translation: AAO73535.2.
AY226577 Genomic DNA. Translation: AAO73536.2.
BC007176 mRNA. Translation: AAH07176.1.
BC079537 mRNA. Translation: AAH79537.1.
AK122198 Transcribed RNA. Translation: BAC65480.3.
AK088590 mRNA. Translation: BAC40439.1.
CCDSiCCDS17613.1. [O88974-4]
CCDS50991.1. [O88974-1]
PIRiT17453.
UniGeneiMm.490259.

Genome annotation databases

UCSCiuc008qjo.2. mouse. [O88974-5]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF091628 mRNA. Translation: AAC43039.1.
AY091600 mRNA. Translation: AAM13922.1.
AF546078 mRNA. Translation: AAN52358.1.
AY226577 Genomic DNA. Translation: AAO73535.2.
AY226577 Genomic DNA. Translation: AAO73536.2.
BC007176 mRNA. Translation: AAH07176.1.
BC079537 mRNA. Translation: AAH79537.1.
AK122198 Transcribed RNA. Translation: BAC65480.3.
AK088590 mRNA. Translation: BAC40439.1.
CCDSiCCDS17613.1. [O88974-4]
CCDS50991.1. [O88974-1]
PIRiT17453.
UniGeneiMm.490259.

3D structure databases

ProteinModelPortaliO88974.
SMRiO88974.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiO88974. 9 interactors.
MINTiMINT-1753431.
STRINGi10090.ENSMUSP00000015841.

PTM databases

iPTMnetiO88974.
PhosphoSitePlusiO88974.

Proteomic databases

EPDiO88974.
MaxQBiO88974.
PaxDbiO88974.
PeptideAtlasiO88974.
PRIDEiO88974.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

UCSCiuc008qjo.2. mouse. [O88974-5]

Organism-specific databases

MGIiMGI:1934229. Setdb1.
RougeiSearch...

Phylogenomic databases

eggNOGiKOG1141. Eukaryota.
COG2940. LUCA.
HOVERGENiHBG061013.
InParanoidiO88974.

Miscellaneous databases

ChiTaRSiSetdb1. mouse.
PROiO88974.
SOURCEiSearch...

Gene expression databases

CleanExiMM_SETDB1.

Family and domain databases

InterProiIPR016177. DNA-bd_dom.
IPR025796. Hist-Lys_N-MeTrfase_SETDB1.
IPR001739. Methyl_CpG_DNA-bd.
IPR003616. Post-SET_dom.
IPR007728. Pre-SET_dom.
IPR001214. SET_dom.
IPR002999. Tudor.
[Graphical view]
PfamiPF01429. MBD. 1 hit.
PF05033. Pre-SET. 1 hit.
PF00856. SET. 1 hit.
[Graphical view]
SMARTiSM00391. MBD. 1 hit.
SM00468. PreSET. 1 hit.
SM00317. SET. 1 hit.
SM00333. TUDOR. 2 hits.
[Graphical view]
SUPFAMiSSF54171. SSF54171. 1 hit.
PROSITEiPS50982. MBD. 1 hit.
PS50868. POST_SET. 1 hit.
PS50867. PRE_SET. 1 hit.
PS51573. SAM_MT43_SUVAR39_1. 1 hit.
PS50280. SET. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiSETB1_MOUSE
AccessioniPrimary (citable) accession number: O88974
Secondary accession number(s): Q6AXH8
, Q78N64, Q78N65, Q80U84, Q8BTV6, Q8CIX7, Q922K1
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 15, 2002
Last sequence update: November 1, 1998
Last modified: November 2, 2016
This is version 149 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.