SETB2_HUMAN
ID SETB2_HUMAN Reviewed; 719 AA.
AC Q96T68; Q5TC65; Q5TC66; Q5W0A7; Q659A7; Q86UD6; Q96AI6;
DT 03-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 03-APR-2007, sequence version 2.
DT 03-AUG-2022, entry version 169.
DE RecName: Full=Histone-lysine N-methyltransferase SETDB2;
DE EC=2.1.1.366 {ECO:0000305|PubMed:20404330};
DE AltName: Full=Chronic lymphocytic leukemia deletion region gene 8 protein;
DE AltName: Full=Lysine N-methyltransferase 1F;
DE AltName: Full=SET domain bifurcated 2;
GN Name=SETDB2; Synonyms=C13orf4, CLLD8, KMT1F;
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 1), AND VARIANT GLY-117.
RX PubMed=11306461;
RA Mabuchi H., Fujii H., Calin G., Alder H., Negrini M., Rassenti L.,
RA Kipps T.J., Bullrich F., Croce C.M.;
RT "Cloning and characterization of CLLD6, CLLD7, and CLLD8, novel candidate
RT genes for leukemogenesis at chromosome 13q14, a region commonly deleted in
RT B-cell chronic lymphocytic leukemia.";
RL Cancer Res. 61:2870-2877(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057823; DOI=10.1038/nature02379;
RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L.,
RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S.,
RA Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Andrews D.T., Ashwell R.I.S., Babbage A.K., Bagguley C.L.,
RA Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C.,
RA Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P.,
RA Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L.,
RA Frankish A.G., Frankland J., French L., Garner P., Garnett J.,
RA Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M.,
RA Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D.,
RA Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D.,
RA Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J.,
RA Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S.,
RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S.,
RA Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R.,
RA Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W.,
RA Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L.,
RA Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R.,
RA Rogers J., Ross M.T.;
RT "The DNA sequence and analysis of human chromosome 13.";
RL Nature 428:522-528(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT MET-473.
RC TISSUE=Colon, and Testis;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 332-719 (ISOFORM 3), AND VARIANT
RP MET-473.
RC TISSUE=Amygdala;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=20404330; DOI=10.1074/jbc.m109.052399;
RA Falandry C., Fourel G., Galy V., Ristriani T., Horard B., Bensimon E.,
RA Salles G., Gilson E., Magdinier F.;
RT "CLLD8/KMT1F is a lysine methyltransferase that is important for chromosome
RT segregation.";
RL J. Biol. Chem. 285:20234-20241(2010).
RN [6]
RP VARIANTS GLY-117 AND MET-473.
RX PubMed=12754510; DOI=10.1038/ng1166;
RA Zhang Y., Leaves N.I., Anderson G.G., Ponting C.P., Broxholme J., Holt R.,
RA Edser P., Bhattacharyya S., Dunham A., Adcock I.M., Pulleyn L.,
RA Barnes P.J., Harper J.I., Abecasis G., Cardon L., White M., Burton J.,
RA Matthews L., Mott R., Ross M., Cox R., Moffatt M.F., Cookson W.O.C.M.;
RT "Positional cloning of a quantitative trait locus on chromosome 13q14 that
RT influences immunoglobulin E levels and asthma.";
RL Nat. Genet. 34:181-186(2003).
CC -!- FUNCTION: Histone methyltransferase involved in left-right axis
CC specification in early development and mitosis. Specifically
CC trimethylates 'Lys-9' of histone H3 (H3K9me3). H3K9me3 is a specific
CC tag for epigenetic transcriptional repression that recruits HP1 (CBX1,
CC CBX3 and/or CBX5) proteins to methylated histones. Contributes to
CC H3K9me3 in both the interspersed repetitive elements and centromere-
CC associated repeats. Plays a role in chromosome condensation and
CC segregation during mitosis. {ECO:0000269|PubMed:20404330}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=N(6),N(6)-dimethyl-L-lysyl(9)-[histone H3] + S-adenosyl-L-
CC methionine = H(+) + N(6),N(6),N(6)-trimethyl-L-lysyl(9)-[histone H3]
CC + S-adenosyl-L-homocysteine; Xref=Rhea:RHEA:60288, Rhea:RHEA-
CC COMP:15538, Rhea:RHEA-COMP:15541, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:57856, ChEBI:CHEBI:59789, ChEBI:CHEBI:61961,
CC ChEBI:CHEBI:61976; EC=2.1.1.366;
CC Evidence={ECO:0000305|PubMed:20404330};
CC -!- INTERACTION:
CC Q96T68; Q8N8R7: ARL14EP; NbExp=4; IntAct=EBI-1222089, EBI-2807994;
CC Q96T68-2; Q8N8R7: ARL14EP; NbExp=6; IntAct=EBI-12346707, EBI-2807994;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:20404330}. Chromosome
CC {ECO:0000305|PubMed:20404330}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q96T68-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96T68-2; Sequence=VSP_008413;
CC Name=3;
CC IsoId=Q96T68-3; Sequence=VSP_024034;
CC -!- TISSUE SPECIFICITY: Ubiquitous. Highest expression in heart, testis and
CC ovary.
CC -!- DOMAIN: In the pre-SET domain, Cys residues bind 3 zinc ions that are
CC arranged in a triangular cluster; some of these Cys residues contribute
CC to the binding of two zinc ions within the cluster. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the class V-like SAM-binding methyltransferase
CC superfamily. {ECO:0000255|PROSITE-ProRule:PRU00190}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAH56265.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305};
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DR EMBL; AF334407; AAK38373.1; -; mRNA.
DR EMBL; AL136218; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL139321; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC017078; AAH17078.1; -; mRNA.
DR EMBL; BC047434; AAH47434.1; -; mRNA.
DR EMBL; AL831937; CAH56265.1; ALT_SEQ; mRNA.
DR CCDS; CCDS53868.1; -. [Q96T68-2]
DR CCDS; CCDS9417.1; -. [Q96T68-1]
DR RefSeq; NP_001153780.1; NM_001160308.2. [Q96T68-2]
DR RefSeq; NP_114121.2; NM_031915.2. [Q96T68-1]
DR PDB; 5TFP; X-ray; 2.00 A; A/B=1-64.
DR PDBsum; 5TFP; -.
DR AlphaFoldDB; Q96T68; -.
DR SMR; Q96T68; -.
DR BioGRID; 123768; 15.
DR IntAct; Q96T68; 12.
DR STRING; 9606.ENSP00000346175; -.
DR iPTMnet; Q96T68; -.
DR PhosphoSitePlus; Q96T68; -.
DR BioMuta; SETDB2; -.
DR DMDM; 143811459; -.
DR jPOST; Q96T68; -.
DR MassIVE; Q96T68; -.
DR PaxDb; Q96T68; -.
DR PeptideAtlas; Q96T68; -.
DR PRIDE; Q96T68; -.
DR ProteomicsDB; 78203; -. [Q96T68-1]
DR ProteomicsDB; 78204; -. [Q96T68-2]
DR ProteomicsDB; 78205; -. [Q96T68-3]
DR Antibodypedia; 23922; 240 antibodies from 36 providers.
DR DNASU; 83852; -.
DR Ensembl; ENST00000317257.12; ENSP00000326477.9; ENSG00000136169.17. [Q96T68-2]
DR Ensembl; ENST00000354234.8; ENSP00000346175.5; ENSG00000136169.17. [Q96T68-1]
DR Ensembl; ENST00000611815.2; ENSP00000482240.2; ENSG00000136169.17. [Q96T68-2]
DR GeneID; 83852; -.
DR KEGG; hsa:83852; -.
DR MANE-Select; ENST00000611815.2; ENSP00000482240.2; NM_001160308.3; NP_001153780.1. [Q96T68-2]
DR UCSC; uc001vcz.4; human. [Q96T68-1]
DR CTD; 83852; -.
DR DisGeNET; 83852; -.
DR GeneCards; SETDB2; -.
DR HGNC; HGNC:20263; SETDB2.
DR HPA; ENSG00000136169; Low tissue specificity.
DR MIM; 607865; gene.
DR neXtProt; NX_Q96T68; -.
DR OpenTargets; ENSG00000136169; -.
DR PharmGKB; PA134956285; -.
DR VEuPathDB; HostDB:ENSG00000136169; -.
DR eggNOG; KOG1141; Eukaryota.
DR GeneTree; ENSGT00940000158209; -.
DR HOGENOM; CLU_003279_2_0_1; -.
DR InParanoid; Q96T68; -.
DR OMA; NQQVFCD; -.
DR OrthoDB; 183716at2759; -.
DR PhylomeDB; Q96T68; -.
DR TreeFam; TF106411; -.
DR BioCyc; MetaCyc:HS06128-MON; -.
DR PathwayCommons; Q96T68; -.
DR Reactome; R-HSA-3214841; PKMTs methylate histone lysines.
DR SignaLink; Q96T68; -.
DR SIGNOR; Q96T68; -.
DR BioGRID-ORCS; 83852; 22 hits in 1117 CRISPR screens.
DR GenomeRNAi; 83852; -.
DR Pharos; Q96T68; Tbio.
DR PRO; PR:Q96T68; -.
DR Proteomes; UP000005640; Chromosome 13.
DR RNAct; Q96T68; protein.
DR Bgee; ENSG00000136169; Expressed in sperm and 181 other tissues.
DR ExpressionAtlas; Q96T68; baseline and differential.
DR Genevisible; Q96T68; HS.
DR GO; GO:0005694; C:chromosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IEA:InterPro.
DR GO; GO:0046974; F:histone methyltransferase activity (H3-K9 specific); IDA:UniProtKB.
DR GO; GO:0018024; F:histone-lysine N-methyltransferase activity; TAS:Reactome.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:0007059; P:chromosome segregation; IMP:UniProtKB.
DR GO; GO:0001947; P:heart looping; ISS:UniProtKB.
DR GO; GO:0070828; P:heterochromatin organization; IBA:GO_Central.
DR GO; GO:0051567; P:histone H3-K9 methylation; IDA:UniProtKB.
DR GO; GO:0070986; P:left/right axis specification; ISS:UniProtKB.
DR GO; GO:0000278; P:mitotic cell cycle; IMP:UniProtKB.
DR GO; GO:0010629; P:negative regulation of gene expression; IBA:GO_Central.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0090309; P:positive regulation of DNA methylation-dependent heterochromatin assembly; IBA:GO_Central.
DR Gene3D; 2.170.270.10; -; 2.
DR InterPro; IPR016177; DNA-bd_dom_sf.
DR InterPro; IPR001739; Methyl_CpG_DNA-bd.
DR InterPro; IPR007728; Pre-SET_dom.
DR InterPro; IPR001214; SET_dom.
DR InterPro; IPR046341; SET_dom_sf.
DR Pfam; PF01429; MBD; 1.
DR Pfam; PF05033; Pre-SET; 1.
DR Pfam; PF00856; SET; 1.
DR SMART; SM00391; MBD; 1.
DR SMART; SM00468; PreSET; 1.
DR SMART; SM00317; SET; 1.
DR SUPFAM; SSF54171; SSF54171; 1.
DR SUPFAM; SSF82199; SSF82199; 1.
DR PROSITE; PS50982; MBD; 1.
DR PROSITE; PS50867; PRE_SET; 1.
DR PROSITE; PS50280; SET; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell cycle; Cell division;
KW Chromatin regulator; Chromosome; Developmental protein; Metal-binding;
KW Methyltransferase; Mitosis; Nucleus; Reference proteome;
KW S-adenosyl-L-methionine; Transferase; Zinc.
FT CHAIN 1..719
FT /note="Histone-lysine N-methyltransferase SETDB2"
FT /id="PRO_0000186088"
FT DOMAIN 157..229
FT /note="MBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00338"
FT DOMAIN 291..364
FT /note="Pre-SET"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00157"
FT DOMAIN 367..694
FT /note="SET"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00190"
FT REGION 72..102
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 508..547
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 519..547
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 293
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250"
FT BINDING 293
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 295
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250"
FT BINDING 299
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250"
FT BINDING 299
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /evidence="ECO:0000250"
FT BINDING 305
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250"
FT BINDING 307
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 345
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 345
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /evidence="ECO:0000250"
FT BINDING 349
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 351
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /evidence="ECO:0000250"
FT BINDING 356
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /evidence="ECO:0000250"
FT BINDING 377..379
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250"
FT BINDING 418
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00190"
FT BINDING 648
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00190"
FT BINDING 651..652
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250"
FT BINDING 654
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="4"
FT /evidence="ECO:0000250"
FT BINDING 707
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="4"
FT /evidence="ECO:0000250"
FT BINDING 709
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="4"
FT /evidence="ECO:0000250"
FT BINDING 714
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="4"
FT /evidence="ECO:0000250"
FT VAR_SEQ 70..81
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_008413"
FT VAR_SEQ 523
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:17974005"
FT /id="VSP_024034"
FT VARIANT 117
FT /note="E -> G (in dbSNP:rs7998427)"
FT /evidence="ECO:0000269|PubMed:11306461,
FT ECO:0000269|PubMed:12754510"
FT /id="VAR_031282"
FT VARIANT 473
FT /note="V -> M (in dbSNP:rs2057413)"
FT /evidence="ECO:0000269|PubMed:12754510,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:17974005"
FT /id="VAR_016976"
FT HELIX 8..17
FT /evidence="ECO:0007829|PDB:5TFP"
FT HELIX 21..40
FT /evidence="ECO:0007829|PDB:5TFP"
FT HELIX 46..60
FT /evidence="ECO:0007829|PDB:5TFP"
FT TURN 61..63
FT /evidence="ECO:0007829|PDB:5TFP"
SQ SEQUENCE 719 AA; 81894 MW; 01CD2CFE5C1D9067 CRC64;
MGEKNGDAKT FWMELEDDGK VDFIFEQVQN VLQSLKQKIK DGSATNKEYI QAMILVNEAT
IINSSTSIKG ASQKEVNAQS SDPMPVTQKE QENKSNAFPS TSCENSFPED CTFLTTENKE
ILSLEDKVVD FREKDSSSNL SYQSHDCSGA CLMKMPLNLK GENPLQLPIK CHFQRRHAKT
NSHSSALHVS YKTPCGRSLR NVEEVFRYLL ETECNFLFTD NFSFNTYVQL ARNYPKQKEV
VSDVDISNGV ESVPISFCNE IDSRKLPQFK YRKTVWPRAY NLTNFSSMFT DSCDCSEGCI
DITKCACLQL TARNAKTSPL SSDKITTGYK YKRLQRQIPT GIYECSLLCK CNRQLCQNRV
VQHGPQVRLQ VFKTEQKGWG VRCLDDIDRG TFVCIYSGRL LSRANTEKSY GIDENGRDEN
TMKNIFSKKR KLEVACSDCE VEVLPLGLET HPRTAKTEKC PPKFSNNPKE LTVETKYDNI
SRIQYHSVIR DPESKTAIFQ HNGKKMEFVS SESVTPEDND GFKPPREHLN SKTKGAQKDS
SSNHVDEFED NLLIESDVID ITKYREETPP RSRCNQATTL DNQNIKKAIE VQIQKPQEGR
STACQRQQVF CDEELLSETK NTSSDSLTKF NKGNVFLLDA TKEGNVGRFL NHSCCPNLLV
QNVFVETHNR NFPLVAFFTN RYVKARTELT WDYGYEAGTV PEKEIFCQCG VNKCRKKIL
