Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
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Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

SETDB1 (Q15047) - Overview - Molecular Target Synopsis

Protein


SETDB1, Histone-lysine N-methyltransferase SETDB1
Enzyme Classification 2.1.1.43
UniProt Q15047

Also Known as SETB1_HUMAN, SETDB1, ESET, KIAA0067, KMT1E

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 (PubMed:12869583, PubMed:17952062). Required for HUSH-mediated heterochromatin formation and gene silencing. Forms a complex with MBD1 and ATF7IP that represses transcription and couples DNA methylation and histone 'Lys-9' trimethylation (PubMed:27732843, PubMed:14536086). Its activity is dependent on MBD1 and is heritably maintained through DNA replication by being recruited by CAF-1 (PubMed:14536086, PubMed:15327775). 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 (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 (By similarity). 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). Part of a complex containing at least CDYL, REST, WIZ, SETDB1, EHMT1 and EHMT2 (PubMed:19061646). 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 (PubMed:15327775). 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 MBD1; interaction is abolished when MBD1 is sumoylated (PubMed:15327775, PubMed:17066076). Interacts with CBX1 and CBX5 (PubMed:15899859). Interacts with DNMT3A and DNMT3B (PubMed:16682412). Interacts with SUMO2. Interacts with CHD7, NLK1 and PPARG (PubMed:17952062). Interacts with MPHOSPH8 (PubMed:20871592). Interacts with ERG (By similarity). Interacts with HDAC1, HDAC2, SIN3A and SIN3B (By similarity). Interacts with ATRX. Forms a complex with ATRX, TRIM28 and ZNF274 (PubMed:27029610). Interacts with RESF1.

6BPI
CRYSTAL STRUCTURE OF SETDB1 TUDOR DOMAIN WITH ARYL TRIAZOLE FRAGMENT PEPTIDE CONJUGATES
RCSB/PDB
Inspect Structure
See all 3D Structures for SETDB1

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: SETDB1 is active in the following subcellular-locations: chromosome, cytoplasm, nucleus.
GO terms: SETDB1 is active in the following subcellular-locations: chromosome, cytoplasm, cytosol, intracellular membrane-bounded organelle, nucleoplasm, nucleus, plasma membrane.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project SETDB1 has gain in 19 cell-lines, loss in 0 cell-lines and no signal in 986 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: MCF7, DU_145, K_562

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: DMS 273, NCI-H1882, AMO-1

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: SK-N-SH, HSMM, MCF-7

(see details)

3D Structures


For SETDB1 there are:
15 structures (16 chains) solved
8 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


SETDB1 has been screened with 14 compounds (15 bioactivities). (see details)