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The dimerization partner, RB-like, E2F and multi-vulval class B (DREAM) complex is a protein complex responsible for the regulation of cell cycle-dependent gene expression. The complex is evolutionarily conserved, although some of its components vary from species to species. In humans, the key proteins in the complex are RBL1 (p107) and RBL2 (p130), both of which are homologs of RB (p105) and bind repressive E2F transcription factors E2F4 and E2F5; DP1, DP2 and DP3, dimerization partners of E2F; and MuvB, which is a complex of LIN9/37/52/54 and RBBP4.
Studies in Drosophila melanogaster ovarian follicle cells identified a protein complex that bound to repeatedly amplifying chorion genes. The complex included genes that had close homology with the MuvB genes such as Mip130, Mip120 and Mip40. These Mip genes were identified as homologues of the MuvB genes LIN9, LIN54, and LIN37 respectively. Further studies in the fly embryo nuclear extracts confirmed the coexistence of these proteins with others such as the RB homologues Rbf1 and Rbf2, and others like E2f and Dp. The protein complex was thus termed as the Drosophila RBF, E2f2 and Mip (dREAM) complex. Disruption of the dREAM complex through RNA interference of the components of dREAM complex led to higher expression of E2f regulated genes that are typically silenced, implicating dREAM's role in gene down-regulation. Later in Drosophila melanogaster, there was also found a testis-specific paralog of the Myb-MuvB/DREAM complex known as tMAC (testis-specific meiotic arrest complex), which is involved in meiotic arrest.
A protein complex similar to dREAM was subsequently identified in C. elegans extract containing DP, RB, and MuvB, and was named as DRM. This complex included mammalian homologues of RB and DP, and other members of the MuvB complex.
The mammalian DREAM complex was identified following immunoprecipitation of p130 with mass-spectrometry analysis. The results showed that p130 was associated with E2F4, E2F5, the dimerization partner DP, and LIN9, LIN54, LIN37, LIN52, and RBBP4 that make up the MuvB complex. Immunoprecipitation of MuvB factors also revealed association of BMYB. Subsequent immunoprecipitation with BMYB yielded all the MuvB core proteins, but not other members of the DREAM complex – p130, p107, E2F4/5 and DP. This indicated that MuvB associated with BMYB to form the BMYB-MuvB complex or with p130/p107, E2F4/5 and DP to form the DREAM complex. The DREAM complex was found prevalent in quiescent or starved cells, and the BMYB-MuvB complex was found in actively dividing cells, hinting at separate functionalities of these two complexes.
MuvB-like complexes were also recently discovered in Arabidoposis that include E2F and MYB orthologs combined with LIN9 and LIN54 orthologs.
Docking of the DREAM complex to promoters is achieved by binding of LIN-54 to regions known as cell cycle genes homology region (CHR). These are specific sequence of nucleotides that are commonly found in the promoters of genes expressed during late S phase or G2/M phase. Docking can also be achieved via E2F proteins binding to sequences known as cell cycle-dependent element sites (CDEs). Some cell cycle dependent genes have been found where both CHRs and CDEs are in proximity to one another. Because p130-E2F4 can form stable associations with the MuvB complex, the proximity of CHRs to CDEs suggests that affinity of binding of the DREAM complex to target genes is cooperatively improved by association with both the binding sites.
When DREAM is docked onto the promoter, p130 is bound to LIN52, and this association inhibits LIN52 binding to chromatin modifier proteins. Therefore, unlike RB-E2F, the DREAM complex is unlikely to directly recruit chromatin modifiers to repress gene expression, although some associations have been suggested. DREAM complex may instead down-regulate gene expression by affecting nucleosome positioning. Compacted DNA at transcription start sites inhibit gene expression by blocking the docking of RNA polymerase. In worms for example, loss of a MuvB complex protein, LIN35, leads to loss of repressive histone associations and high expression of cell cycle dependent genes. However, direct evidence for the link between repressive and the DREAM complex remains to be elucidated.
Other components have been shown to be phosphorylated for DREAM complex assembly to occur. Of these, LIN52 phosphorylation on its S28 residue is the most well-understood. Substitution of this serine to alanine led to reduced binding of the MuvB core to p130 and impaired the ability of cells to enter quiescence. This indicates that LIN52 S28 phosphorylation is required for proper association and function of the DREAM complex via binding with p130. One known regulator of phosphorylation of the S28 residue is the DYRK1A. The loss of this kinase leads to decreased phosphorylation of the S28 residue and association of p130 with MuvB. DYRK1A was also found to degrade cyclin D1, which would increase p21 levels – both of which contribute to cell cycle exit.
The DREAM complex was also shown to regulate cytokinesis through GAS2L3.
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