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Reviewed, UniProtKB/Swiss-Prot Q15047 (SETB1_HUMAN)

Last modified November 25, 2008. Version 96. Feed History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    Histone-lysine N-methyltransferase SETDB1
    EC=2.1.1.43
Alternative name(s):
    SET domain bifurcated 1
    ERG-associated protein with SET domain
      Short name=ESET
    Histone H3-K9 methyltransferase 4
    H3-K9-HMTase 4
    Lysine N-methyltransferase 1E
Gene names
Name: SETDB1
Synonyms: KIAA0067, KMT1E
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1291 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
Protein existenceEvidence at protein level.

General annotation (Comments)

Function

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.

Catalytic activity

S-adenosyl-L-methionine + histone L-lysine = S-adenosyl-L-homocysteine + histone N(6)-methyl-L-lysine.

Subunit structure

Interacts with MBD1; interaction is abolished when MBD1 is sumoylated. 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'. 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. Interacts with ERG, TRIM28/TIF1B, CBX1, CBX5, DNMT3A, HDAC1, HDAC2, SIN3A, SIN3B, DNMT3B and SUMO2.

Subcellular location

Nucleus. Note= Associated with non-pericentromeric regions of chromatin. Excluded from nucleoli and islands of condensed chromatin.

Tissue specificity

Widely expressed. High expression in testis.

Domain

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.

Miscellaneous

Isoform 2 lacks all domains required for histone methyltransferase activity.

Highly up-regulated in Huntington disease patients, suggesting that participates in the altered chromatin modulation and transcription dysfunction observed in Huntington disease. Its down-regulation has salubrious effects on patients, suggesting that it may be a promising treatment in Huntington disease patients.

Sequence similarities

Belongs to the histone-lysine methyltransferase family. Suvar3-9 subfamily.

Contains 1 MBD (methyl-CpG-binding) domain.

Contains 1 post-SET domain.

Contains 1 pre-SET domain.

Contains 1 SET domain.

Contains 2 Tudor domains.

Sequence caution

The sequence CAI13325.1 differs from that shown. Reason: Erroneous gene model prediction.

The sequence CAI13326.1 differs from that shown. Reason: Erroneous gene model prediction.

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q15047-1)

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.
Isoform 2 (identifier: Q15047-2)

The sequence of this isoform differs from the canonical sequence as follows:
     381-397: DDKRCEWIYRGSTRLEP → VLFFSTILEAEVGGGGT
     398-1291: Missing.
Notes: No experimental confirmation available.
Isoform 3 (identifier: Q15047-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1254-1254: Missing.
Notes: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 12911291Histone-lysine N-methyltransferase SETDB1
PRO_0000186064

Regions

Domain257 – 32064Tudor 1
Domain347 – 40357Tudor 2
Domain594 – 66572MBD
Domain727 – 80074Pre-SET
Domain802 – 1270469SET
Domain1275 – 129117Post-SET
Coiled coil18 – 6447 Potential

Amino acid modifications

Modified residue8381Phosphothreonine
Modified residue10661Phosphoserine
Modified residue11791Phosphoserine
Modified residue11801Phosphothreonine
Modified residue11901Phosphoserine

Natural variations

Alternative sequence381 – 39717DDKRC…TRLEP → VLFFSTILEAEVGGGGT in isoform 2.
VSP_002217
Alternative sequence398 – 1291894Missing in isoform 2.
VSP_002218
Alternative sequence12541Missing in isoform 3.
VSP_034600
Natural variant2361N → S: dbSNP rs2271075.
VAR_014284
Natural variant5061P → S: dbSNP rs17852587.
VAR_031281
Natural variant8241A → G: dbSNP rs2691551.
VAR_014286
Natural variant8241A → P: dbSNP rs2814054.
VAR_014285

Experimental info

Mutagenesis729 – 7313CDC → LDP: Abolishes methyltransferase activity
Mutagenesis12241H → K: Abolishes methyltransferase activity
Mutagenesis12261C → A: Abolishes methyltransferase activity
Mutagenesis12791C → Y: Abolishes methyltransferase activity

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: D8841B4C41B911C5

FASTA1,291143,157
        10         20         30         40         50         60 
MSSLPGCIGL DAATATVESE EIAELQQAVV EELGISMEEL RHFIDEELEK MDCVQQRKKQ 

        70         80         90        100        110        120 
LAELETWVIQ KESEVAHVDQ LFDDASRAVT NCESLVKDFY SKLGLQYRDS SSEDESSRPT 

       130        140        150        160        170        180 
EIIEIPDEDD DVLSIDSGDA GSRTPKDQKL REAMAALRKS AQDVQKFMDA VNKKSSSQDL 

       190        200        210        220        230        240 
HKGTLSQMSG ELSKDGDLIV SMRILGKKRT KTWHKGTLIA IQTVGPGKKY KVKFDNKGKS 

       250        260        270        280        290        300 
LLSGNHIAYD YHPPADKLYV GSRVVAKYKD GNQVWLYAGI VAETPNVKNK LRFLIFFDDG 

       310        320        330        340        350        360 
YASYVTQSEL YPICRPLKKT WEDIEDISCR DFIEEYVTAY PNRPMVLLKS GQLIKTEWEG 

       370        380        390        400        410        420 
TWWKSRVEEV DGSLVRILFL DDKRCEWIYR GSTRLEPMFS MKTSSASALE KKQGQLRTRP 

       430        440        450        460        470        480 
NMGAVRSKGP VVQYTQDLTG TGTQFKPVEP PQPTAPPAPP FPPAPPLSPQ AGDSDLESQL 

       490        500        510        520        530        540 
AQSRKQVAKK STSFRPGSVG SGHSSPTSPA LSENVSGGKP GINQTYRSPL GSTASAPAPS 

       550        560        570        580        590        600 
ALPAPPAPPV FHGMLERAPA EPSYRAPMEK LFYLPHVCSY TCLSRVRPMR NEQYRGKNPL 

       610        620        630        640        650        660 
LVPLLYDFRR MTARRRVNRK MGFHVIYKTP CGLCLRTMQE IERYLFETGC DFLFLEMFCL 

       670        680        690        700        710        720 
DPYVLVDRKF QPYKPFYYIL DITYGKEDVP LSCVNEIDTT PPPQVAYSKE RIPGKGVFIN 

       730        740        750        760        770        780 
TGPEFLVGCD CKDGCRDKSK CACHQLTIQA TACTPGGQIN PNSGYQYKRL EECLPTGVYE 

       790        800        810        820        830        840 
CNKRCKCDPN MCTNRLVQHG LQVRLQLFKT QNKGWGIRCL DDIAKGSFVC IYAGKILTDD 

       850        860        870        880        890        900 
FADKEGLEMG DEYFANLDHI ESVENFKEGY ESDAPCSSDS SGVDLKDQED GNSGTEDPEE 

       910        920        930        940        950        960 
SNDDSSDDNF CKDEDFSTSS VWRSYATRRQ TRGQKENGLS ETTSKDSHPP DLGPPHIPVP 

       970        980        990       1000       1010       1020 
PSIPVGGCNP PSSEETPKNK VASWLSCNSV SEGGFADSDS HSSFKTNEGG EGRAGGSRME 

      1030       1040       1050       1060       1070       1080 
AEKASTSGLG IKDEGDIKQA KKEDTDDRNK MSVVTESSRN YGYNPSPVKP EGLRRPPSKT 

      1090       1100       1110       1120       1130       1140 
SMHQSRRLMA SAQSNPDDVL TLSSSTESEG ESGTSRKPTA GQTSATAVDS DDIQTISSGS 

      1150       1160       1170       1180       1190       1200 
EGDDFEDKKN MTGPMKRQVA VKSTRGFALK STHGIAIKST NMASVDKGES APVRKNTRQF 

      1210       1220       1230       1240       1250       1260 
YDGEESCYII DAKLEGNLGR YLNHSCSPNL FVQNVFVDTH DLRFPWVAFF ASKRIRAGTE 

      1270       1280       1290 
LTWDYNYEVG SVEGKELLCC CGAIECRGRL L 

« Hide

Isoform 2 [UniParc].

Checksum: A880C9152E11A900
Show »

39744,689
Isoform 3 [UniParc].

Checksum: BBF5516339BE6C17
Show »

1,290143,001

References

« Hide 'large scale' references
[1]"Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1."
Nomura N., Nagase T., Miyajima N., Sazuka T., Tanaka A., Sato S., Seki N., Kawarabayasi Y., Ishikawa K., Tabata S.
DNA Res. 1:223-229(1994) [PubMed: 7584044] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Bone marrow.
[2]"The DNA sequence and biological annotation of human chromosome 1."
Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. expand/collapse author list , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.
Nature 441:315-321(2006) [PubMed: 16710414] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (DEC-2006) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3), VARIANT SER-506.
Tissue: Muscle and Uterus.
[5]"SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins."
Schultz D.C., Ayyanathan K., Negorev D., Maul G.G., Rauscher F.J. III
Genes Dev. 16:919-932(2002) [PubMed: 11959841] [Abstract]
Cited for: CHARACTERIZATION, MUTAGENESIS OF 729-CYS--CYS-731; HIS-1224; CYS-1226 AND CYS-1279, INTERACTION WITH TRIM28.
[6]"Regulated recruitment of HP1 to a euchromatic gene induces mitotically heritable, epigenetic gene silencing: a mammalian cell culture model of gene variegation."
Ayyanathan K., Lechner M.S., Bell P., Maul G.G., Schultz D.C., Yamada Y., Tanaka K., Torigoe K., Rauscher F.J. III
Genes Dev. 17:1855-1869(2003) [PubMed: 12869583] [Abstract]
Cited for: FUNCTION.
[7]"mAM facilitates conversion by ESET of dimethyl to trimethyl lysine 9 of histone H3 to cause transcriptional repression."
Wang H., An W., Cao R., Xia L., Erdjument-Bromage H., Chatton B., Tempst P., Roeder R.G., Zhang Y.
Mol. Cell 12:475-487(2003) [PubMed: 14536086] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY, FUNCTION, INTERACTION WITH ATF7IP.
[8]"Methyl-CpG binding protein MBD1 couples histone H3 methylation at lysine 9 by SETDB1 to DNA replication and chromatin assembly."
Sarraf S.A., Stancheva I.
Mol. Cell 15:595-605(2004) [PubMed: 15327775] [Abstract]
Cited for: FUNCTION, INTERACTION WITH MBD1 AND CHAF1A.
[9]"In vivo HP1 targeting causes large-scale chromatin condensation and enhanced histone lysine methylation."
Verschure P.J., van der Kraan I., de Leeuw W., van der Vlag J., Carpenter A.E., Belmont A.S., van Driel R.
Mol. Cell. Biol. 25:4552-4564(2005) [PubMed: 15899859] [Abstract]
Cited for: INTERACTION WITH CBX1 AND CBX5.
[10]"Global phosphoproteome analysis on human HepG2 hepatocytes using reversed-phase diagonal LC."
Gevaert K., Staes A., Van Damme J., De Groot S., Hugelier K., Demol H., Martens L., Goethals M., Vandekerckhove J.
Proteomics 5:3589-3599(2005) [PubMed: 16097034] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-838, MASS SPECTROMETRY.
Tissue: Hepatocyte.
[11]"Regulation of MBD1-mediated transcriptional repression by SUMO and PIAS proteins."
Lyst M.J., Nan X., Stancheva I.
EMBO J. 25:5317-5328(2006) [PubMed: 17066076] [Abstract]
Cited for: INTERACTION WITH MBD1.
[12]"Transcriptional repression and heterochromatin formation by MBD1 and MCAF/AM family proteins."
Ichimura T., Watanabe S., Sakamoto Y., Aoto T., Fujita N., Nakao M.
J. Biol. Chem. 280:13928-13935(2005) [PubMed: 15691849] [Abstract]
Cited for: INTERACTION WITH ATF7IP AND ATF7IP2.
[13]"The histone methyltransferase SETDB1 and the DNA methyltransferase DNMT3A interact directly and localize to promoters silenced in cancer cells."
Li H., Rauch T., Chen Z.-X., Szabo P.E., Riggs A.D., Pfeifer G.P.
J. Biol. Chem. 281:19489-19500(2006) [PubMed: 16682412] [Abstract]
Cited for: INTERACTION WITH DNMT3A AND DNMT3B.
[14]"NXP-2 association with SUMO-2 depends on lysines required for transcriptional repression."
Rosendorff A., Sakakibara S., Lu S., Kieff E., Xuan Y., DiBacco A., Shi Y., Shi Y., Gill G.
Proc. Natl. Acad. Sci. U.S.A. 103:5308-5313(2006) [PubMed: 16567619] [Abstract]
Cited for: INTERACTION WITH SUMO2.
[15]"ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease."
Ryu H., Lee J., Hagerty S.W., Soh B.Y., McAlpin S.E., Cormier K.A., Smith K.M., Ferrante R.J.
Proc. Natl. Acad. Sci. U.S.A. 103:19176-19181(2006) [PubMed: 17142323] [Abstract]
Cited for: EXPRESSION IN HUNTINGTON DISEASE.
[16]"Global proteomic profiling of phosphopeptides using electron transfer dissociation tandem mass spectrometry."
Molina H., Horn D.M., Tang N., Mathivanan S., Pandey A.
Proc. Natl. Acad. Sci. U.S.A. 104:2199-2204(2007) [PubMed: 17287340] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1179; THR-1180 AND SER-1190, MASS SPECTROMETRY.
[17]"Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis."
Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III
J. Proteome Res. 7:1346-1351(2008) [PubMed: 18220336] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1066, MASS SPECTROMETRY.
[18]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1066, MASS SPECTROMETRY.

Cross-references

Sequence databases

D31891 mRNA. Translation: BAA06689.2. Different initiation.
AL590133 Genomic DNA. Translation: CAI13325.1. Sequence problems.
AL590133 Genomic DNA. Translation: CAI13326.1. Sequence problems.
AL590133 Genomic DNA. Translation: CAI13327.1.
AL590133 Genomic DNA. Translation: CAI13328.1.
CH471121 Genomic DNA. Translation: EAW53506.1.
BC009362 mRNA. Translation: AAH09362.1.
BC028671 mRNA. Translation: AAH28671.1.
RefSeqNP_036564.2.
UniGeneHs.643565

3D structure databases

EntryMethodResolution (Å)ChainPositionsPDBsum
3DLMX-ray1.77A196-402[»]
ModBaseSearch...