SETDB1 is a member of the histone-lysine N-methyltransferase Suvar3-9 subfamily. Members of this subfamily trimethylate '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 []. This enzyme 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. It probably forms a complex with MBD1 and ATF7IP that represses transcription and couples DNA methylation and histone 'Lys-9' trimethylation [].Methyltransferases (EC [intenz:2.1.1.-]) constitute an important class of enzymes present in every life form. They transfer a methyl group most frequently from S-adenosyl L-methionine (SAM or AdoMet) to a nucleophilic acceptor such as oxygen leading to S-adenosyl-L-homocysteine (AdoHcy) and a methylated molecule [, , ]. All these enzymes have in common a conserved region of about 130 amino acid residues that allow them to bind SAM []. The substrates that are methylated by these enzymes cover virtually every kind of biomolecules ranging from small molecules, to lipids, proteins and nucleic acids [, , ]. Methyltransferase are therefore involved in many essential cellular processes including biosynthesis, signal transduction, protein repair, chromatin regulation and gene silencing [, , ]. More than 230 families of methyltransferases have been described so far, of which more than 220 use SAM as the methyl donor.
This domain is often found in the N-terminal region of proteins carrying the SET domain, such as the SETDB1 protein from Humans. SETDB1 is a histone methyltransferase that suppresses gene expression and modulates heterochromatin formation through H3K9me2/3 [].
This is the second TUDOR domain found in SETDB1 enzymes () from mammals, also known as Eggless in Drosophila []. In Drosophila, SetdB1 (Egg) is important for oogenesis and the silencing of chromosome 4 []. SET domain, bifurcated 1 (SETDB1) is a histone methyltransferase (HMT) that methylates lysine 9 on histone H3 (H3K9). The enzymatic activity of SETDB1, in association with MBD1-containing chromatin-associated factor 1 (MCAF1), converts H3K9me2 to H3K9me3 and represses subsequent transcription. SETDB1 is amplified in cancers such as melanoma and lung cancer, and increased expression of SETDB1 promotes tumorigenesis in a zebrafish melanoma model. In addition, SETDB1 is required for endogenous retrovirus silencing during early embryogenesis, inhibition of adipocyte differentiation, and differentiation of mesenchymal cells into osteoblasts []. The tandem Tudor domains in the N-terminal region are involved in protein-protein interactions [].
This is the first TUDOR domain found in SETDB1 enzymes () from animals, also known as Eggless in Drosophila []. In Drosophila, SetdB1 (Egg) is important for oogenesis and the silencing of chromosome 4 []. SET domain, bifurcated 1 (SETDB1) is a histone methyltransferase (HMT) that methylates lysine 9 on histone H3 (H3K9). The enzymatic activity of SETDB1, in association with MBD1-containing chromatin-associated factor 1 (MCAF1), converts H3K9me2 to H3K9me3 and represses subsequent transcription. SETDB1 is amplified in cancers such as melanoma and lung cancer, and increased expression of SETDB1 promotes tumorigenesis in a zebrafish melanoma model. In addition, SETDB1 is required for endogenous retrovirus silencing during early embryogenesis, inhibition of adipocyte differentiation, and differentiation of mesenchymal cells into osteoblasts []. The tandem Tudor domains in the N-terminal region are involved in protein-protein interactions [].
TASOR is a key component of the HUSH complex, a vertebrate-specific multiprotein complex that mediates epigenetic repression of both exogenous and endogenous genetic elements [, , ]. The HUSH complex regulates H3K9me3 deposition by promoting recruitment of SETDB1 and also recruits MORC2 to compact chromatin [, , ]. The HUSH complex represses L1 retrotransposons and is also involved in the silencing of unintegrated retroviral DNA by being recruited by ZNF638: some part of the retroviral DNA formed immediately after infection remains unintegrated in the host genome and is transcriptionally repressed []. TASOR is crucial in early embryonic development [], and contains a catalytically-inactive PARP domain, necessary for epigenetic regulation of target elements.
This domain is found in eukaryotes, and is approximately 170 amino acids in length. Proteins containing this domain include TASOR and TASOR 2 (also known as FAM208A/B) proteins []. TASOR is a key component of the HUSH complex, a vertebrate-specific multiprotein complex that mediates epigenetic repression of both exogenous and endogenous genetic elements [, , ]. The HUSH complex regulates H3K9me3 deposition by promoting recruitment of SETDB1 and also recruits MORC2 to compact chromatin [, , ]. The HUSH complex represses L1 retrotransposons and is also involved in the silencing of unintegrated retroviral DNA by being recruited by ZNF638: some part of the retroviral DNA formed immediately after infection remains unintegrated in the host genome and is transcriptionally repressed []. TASOR is crucial in early embryonic development [], and contains a catalytically-inactive PARP domain, necessary for epigenetic regulation of target elements.
Methylation at CpG dinucleotide, the most common DNA modification ineukaryotes, has been correlated with gene silencing associated with variousphenomena such as genomic imprinting, transposon and chromosome X inactivation, differentiation, and cancer. Effects of DNA methylation are mediated through proteins which bind to symmetrically methylated CpGs. Such proteins contain a specific domain of ~70 residues, the methyl-CpG-binding domain (MBD), which is linked to additional domains associated with chromatin, such as the bromodomain, the AT hook motif,the SET domain, or the PHD finger. MBD-containing proteins appear to act as structural proteins, which recruit a variety of histone deacetylase (HDAC) complexes and chromatin remodelling factors, leading to chromatin compaction and, consequently, to transcriptional repression. The MBD of MeCP2, MBD1, MBD2, MBD4 and BAZ2 mediates binding to DNA, in case of MeCP2, MBD1 and MBD2 preferentially to methylated CpG. In case of human MBD3 and SETDB1 the MBD has been shown to mediate protein-protein interactions [, ].The MBD folds into an alpha/beta sandwich structure comprising a layer oftwisted beta sheet, backed by another layer formed by the alpha1 helix and ahairpin loop at the C terminus. These layers are both amphipathic, with the alpha1 helix and the beta sheet lying parallel and the hydrophobic faces tightly packed against each other. The beta sheet is composed of two long inner strands (beta2 and beta3) sandwiched by two shorter outer strands (beta1 and beta4) [].
