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QuickView for Histone H3-K9 methyltransferase (biogroup)
- Description:
- Members of this family trimethylate 'Lys-9' of histone H3 using monomethylated H3 'Lys-9' as substrate. It also weakly methylates histone H1 (in vitro). 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 heterochromatin regions, thereby playing a central role in the establishment of constitutive heterochromatin at pericentric and telomere regions. H3 'Lys-9' trimethylation is also required to direct DNA methylation at pericentric repeats. SUV39H1 (the human ortholog) is targeted to histone H3 via its interaction with RB1 and is involved in many processes, such as repression of MYOD1-stimulated differentiation, regulation of the control switch for exiting the cell cycle and entering differentiation, repression by the PML-RARA fusion protein, BMP-induced repression, repression of switch recombination to IgA and regulation of telomere length. SUV39H1 is a component of the eNoSC (energy-dependent nucleolar silencing) complex, a complex that mediates silencing of rDNA in response to intracellular energy status and acts by recruiting histone-modifying enzymes. The eNoSC complex is able to sense the energy status of cell: upon glucose starvation, elevation of NAD+/NADP+ ratio activates SIRT1, leading to histone H3 deacetylation followed by dimethylation of H3 at 'Lys-9' (H3K9me2) by SUV39H1 and the formation of silent chromatin in the rDNA locus. The activity of this enzyme has been mapped to the SET domain and the adjacent cysteine-rich regions. The SET domain was originally identified in Su(var)3-9, E(z) and Trithorax genes in Drosophila melanogaster (Fruit fly). The sequence conservation pattern and structure analysis of the SET domain provides clues regarding the possible active site residues of the domain. There are three conserved sequence motifs in most of the SET domains. The N-terminal motif (I) has characteristic glycines. The central motif (II) has a distinct pattern of polar and charged residues (Asn, His). The C-terminal conserved motif (III) has a characteristic dyad of polar residues. It has been shown that deregulated SUV39H1 interferes at multiple levels with mammalian higher-order chromatin organisation and these properties depend primarily on the SET domain. Methyltransferases (EC 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.
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