Cyclin-D1-binding protein 1 (CCNDBP1, also known as GCIP) is a helix-loop-helix protein that may negatively regulate cell cycle progression and could function in tumour suppression []. It may act, at least in part, via inhibition of the cyclin-D1/CDK4 complex, thereby preventing phosphorylation of RB1 and blocking E2F-dependent transcription [, ].
This group represents adenoviral early E1A proteins. The E1A protein is responsible for the transcriptional activation of the early genes with in the viral genome at the start of the infection process as well as some cellular genes [].E1A disrupts the function of host retinoblastoma protein RB1/pRb, which is a key regulator of the cell cycle []. It also induces the disassembly of the E2F1 transcription factors from RB1 by direct competition for the same binding site on RB1, with subsequent transcriptional activation of E2F1-regulated S-phase genes []. Inactivation of the ability of RB1 to arrest the cell cycle is critical for cellular transformation, uncontrolled cellular growth and proliferation induced by viral infection. The stimulation of the progression from G1 to S phase allows the virus to efficiently use the cellular DNA replicating machinery to achieve viral genome replication.
Augurin is alternatively named oesophageal cancer-related gene 4 protein. The function of this family of transmembrane proteins is to induce the senescence of oligodendrocyte and neural precursor cells, characterised by G1 arrest, RB1 dephosphorylation and accelerated CCND1 and CCND3 proteasomal degradation [, ]. Augurin is a posible hormone that has been found to stimulate the release of adrenocorticotropic hormone (ACTH) via the release of hypothalamic corticotrophin-releasing factor (CRF) [].
Mortality factor 4-like protein 2 (MORF4L2 or MRGX) is a component of the NuA4 histone acetyltransferase complex []and the MSIN3A complex which acts to repress transcription by deacetylation of nucleosomal histones []. MRGX interacts with MRFAP1 and RB1 and represses the B-myb promoter in EJ cells but activates it in HeLa cells []. MRGX contains an MRG domain.The NuA4 histone acetyltransferase complex (also known as the TRRAP/TIP60-containing histone acetyltransferase complex) acetylates nucleosomal histones H4 and H2A thereby activating selected genes for transcription and is a a key regulator of transcription, cellular response to DNA damage and cell cycle control []. In yeast, where the complex was first identified, NuA4 consists of at least ACT1, ARP4, YAF9, VID21, SWC4, EAF3, EAF5, EAF6, EAF7, EPL1, ESA1, TRA1 and YNG2 []. In humans, the complex is composed of the histone acetyltransferase KAT5 (also known as TIP60) plus the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, MAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6 [].
This entry represents the SET domain of SET and MYND domain-containing protein 2 (SMYD2). SMYD2 functions as a histone methyltransferase that methylates both histones and non-histone proteins, including p53/TP53 and RB1 [, ]. It specifically methylates histone H3 'Lys-4' (H3K4me) and dimethylates histone H3 'Lys-36' (H3K36me2). It plays a role in myofilament organisation in both skeletal and cardiac muscles via Hsp90 methylation []. SMYD2 overexpression is associated with tumour cell proliferation and a worse outcome in human papillomavirus-unrelated nonmultiple head and neck carcinomas []. It regulates leukemia cell growth such that diminished SMYD2 expression upregulates SET7/9, thereby possibly shifting leukemia cells from growth to quiescence state associated with resistance to DNA damage associated with Acute Myeloid Leukemia (AML) [].The SMYD family consists of five members including SMYD1/2/3/4/5. They contain two highly conserved structural and functional domains, the SET and MYND domains. The SET domain is involved in lysine methylation, while the MYND domain is involved in protein-protein interaction. They are essential in several mammalian developmental pathways [, , , ].
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 [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.
