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Details on Person UniProt:Q15047-3 SETDB1
| Class:Id | ReferenceIsoform:386069 |
|---|---|
| _chainChangeLog | chain:1-1291 added on Sat February 7 2015 |
| _displayName | UniProt:Q15047-3 SETDB1 |
| _timestamp | 2026-02-20 23:11:03 |
| chain | chain:1-1291 |
| checksum | D8841B4C41B911C5 |
| comment | FUNCTION Histone methyltransferase that specifically trimethylates 'Lys-9' of histone H3 (H3K9me3) (PubMed:11959841, PubMed:12869583, PubMed:14536086, PubMed:27237050, PubMed:39096901). H3 'Lys-9' trimethylation represents a specific tag for epigenetic transcriptional repression by recruiting HP1 (CBX1, CBX3 and/or CBX5) proteins to methylated histones (PubMed:11959841, PubMed:12869583, PubMed:14536086, PubMed:27237050, PubMed:39096901). Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes (PubMed:12869583, PubMed:14536086, PubMed:27237050, PubMed:39096901). H3 'Lys-9' trimethylation is coordinated with DNA methylation (PubMed:12869583, PubMed:14536086, PubMed:27237050, PubMed:39096901). Forms a complex with MBD1 and ATF7IP that represses transcription and couples DNA methylation and histone 'Lys-9' trimethylation (PubMed:14536086). Its activity is dependent on MBD1 and is heritably maintained through DNA replication by being recruited by CAF-1 (PubMed:14536086). SETDB1 is targeted to histone H3 by TRIM28/TIF1B, a factor recruited by KRAB zinc-finger proteins (PubMed:24623306). Required for HUSH-mediated heterochromatin formation and gene silencing (PubMed:27732843). 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 (PubMed:24623306). Required to maintain a transcriptionally repressive state of genes in undifferentiated embryonic stem cells (ESCs) (PubMed:24623306). In ESCs, in collaboration with TRIM28, is also required for H3K9me3 and silencing of endogenous and introduced retroviruses in a DNA-methylation independent-pathway (PubMed:37938770). Associates at promoter regions of tumor suppressor genes (TSGs) leading to their gene silencing (PubMed:24623306). 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 (PubMed:27029610). Also catalyzes mono- and dimethylation of 'Lys-9' of free histone H3 (H3K9me1 and H3K9me2) during translation in the cytoplasm, which is then transported to the nucleus and incorporated into nucleosomes (PubMed:26405197).FUNCTION Lacks all domains required for histone methyltransferase activity.CATALYTIC ACTIVITY N(6),N(6)-dimethyl-L-lysyl(9)-[histone H3] + S-adenosyl-L-methionine = N(6),N(6),N(6)-trimethyl-L-lysyl(9)-[histone H3] + S-adenosyl-L-homocysteine + H(+)CATALYTIC ACTIVITY L-lysyl(9)-[histone H3] + S-adenosyl-L-methionine = N(6)-methyl-L-lysyl(9)-[histone H3] + S-adenosyl-L-homocysteine + H(+)CATALYTIC ACTIVITY L-lysyl(9)-[histone H3] + 2 S-adenosyl-L-methionine = N(6),N(6)-dimethyl-L-lysyl(9)-[histone H3] + 2 S-adenosyl-L-homocysteine + 2 H(+)BIOPHYSICOCHEMICAL PROPERTIES Part of a complex containing at least CDYL, REST, WIZ, SETDB1, EHMT1 and EHMT2 (PubMed:19061646). Forms a complex with ATRX, TRIM28 and ZNF274 (PubMed:27029610). Probably part of a corepressor complex containing ZNF304, TRIM28, SETDB1 and DNMT1 (PubMed:24623306). Interacts with TRIM28/TIF1B (PubMed:11959841). Interacts with ATF7IP and ATF7IP2; the interaction with ATF7IP protects SETDB1 from proteasomal degradation and is required to stimulate histone methyltransferase activity and facilitate the conversion of dimethylated to trimethylated H3 'Lys-9' (PubMed:14536086, PubMed:15691849). Interacts with CBX1 and CBX5 (PubMed:15899859). Interacts with DNMT3A and DNMT3B (PubMed:16682412). Interacts with SUMO2. Interacts with MPHOSPH8 (PubMed:20871592). Interacts with ERG (By similarity). Interacts with HDAC1, HDAC2, SIN3A and SIN3B (By similarity). Interacts with ATRX. Interacts with RESF1 (By similarity). Interacts with ZNF638 (PubMed:30487602). Interacts with TASOR (By similarity). Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression (PubMed:32051553). Interacts with PHF13; the interaction probably enhances SETDB1 chromatin-associated levels and activity (PubMed:23034801). Interacts with VRK1 (PubMed:37179361).INTERACTION Associated with non-pericentromeric regions of chromatin (PubMed:27029610). Recruited to H3K9me and H3K19ac marks on chromatin (PubMed:29234025). Excluded from nucleoli and islands of condensed chromatin (PubMed:27732843).ALTERNATIVE PRODUCTS Widely expressed. High expression in testis.DOMAIN The Tudor domains recognize and bind histone H3 methylated at 'Lys-9' and acetylated at 'Lys-14' (H3K9me and H3K19ac, respectively) (PubMed:29234025). The Tudor domain 3 specifically recognizes H3K9me1 or H3K9me2, while the Tudor domain 2 specifically recognizes H3K9me3 (PubMed:29234025). H3K14ac is recognized by residues from Tudor domains 2 and 3, and the linker between them (PubMed:29234025). The Tudor domain 1 contains an incomplete aromatic cage and is inactive (PubMed:29234025).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.DOMAIN 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.PTM Degraded by the proteasome, shielded by interaction with ATF7IP.PTM Monoubiquitinated at Lys-867 by E2 enzymes of the UBE2E family. The conjugated-Ub is protected from deubiquitination by the SET domain. Monoubiquitination at Lys-867 is required for catalytic activity, H3K9 methylation and endogenous retrovirus silencing.MISCELLANEOUS 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.SIMILARITY Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. Suvar3-9 subfamily.CAUTION Was reported to be recruited by MBD1, during DNA replication, to form a S phase-specific complex that would facilitate methylation of H3 'Lys-9' during replication-coupled chromatin assembly and would be at least composed of the CAF-1 subunit CHAF1A, MBD1 and SETDB1 (PubMed:15327775, PubMed:17066076). However, these papers have been retracted because some data, results and conclusions are not reliable (PubMed:30849389, PubMed:31612521).CAUTION Was reported to trimethylate H3 'Lys-9', to interact with CHD7, NLK1 and PPARG and to be phosphorylated at Thr-796 (PubMed:17952062). However, this work was later retracted although its role in H3 'Lys-9' trimethylation is supported by other papers (PubMed:25358353).SEQUENCE CAUTION Extended N-terminus. |
| created | [InstanceEdit:384350] Kanapin, AA, 2008-11-26 14:00:39 |
| description | recommendedName: fullName evidence="43"Histone-lysine N-methyltransferase SETDB1 ecNumber evidence="10 12"2.1.1.366 alternativeName: ERG-associated protein with SET domain shortName evidence="40"ESET alternativeName: Histone H3-K9 methyltransferase 4 shortName: H3-K9-HMTase 4 alternativeName: Lysine N-methyltransferase 1E alternativeName: SET domain bifurcated 1 |
| geneName | SETDB1 ESET KIAA0067 KMT1E |
| identifier | Q15047 |
| isoformParent | |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Alternative splicing Chromatin regulator Chromosome Coiled coil Cytoplasm Isopeptide bond Metal-binding Methylation Methyltransferase Nucleus Phosphoprotein Proteomics identification Reference proteome Repeat Repressor S-adenosyl-L-methionine Transcription Transcription regulation Transferase Ubl conjugation Zinc |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9862192] Weiser, Joel, 2024-02-26 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9939033] Weiser, Joel, 2025-02-21 [InstanceEdit:9983091] Weiser, Joel, 2026-02-20 |
| name | SETDB1 |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:8993309] ENSEMBL:ENSG00000143379 SETDB1 [Homo sapiens] |
| secondaryIdentifier | SETB1_HUMAN A6NEW2 Q5SZD8 Q5SZD9 Q5SZE0 Q5SZE7 Q96GM9 |
| sequenceLength | 1291 |
| species | [Species:48887] Homo sapiens |
| variantIdentifier | Q15047-3 |
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No pathways have been reviewed or authored by UniProt:Q15047-3 SETDB1 (386069)
