The DREAM complex: master coordinator of cell cycle-dependent gene expression

Abstract

The dimerization partner, RB-like, E2F and multi-vulval class B (DREAM) complex provides a previously unsuspected unifying role in the cell cycle by directly linking p130, p107, E2F, BMYB and forkhead box protein M1. DREAM mediates gene repression during the G0 phase and coordinates periodic gene expression with peaks during the G1/S and G2/M phases. Perturbations in DREAM complex regulation shift the balance from quiescence towards proliferation and contribute to the increased mitotic gene expression levels that are frequently observed in cancers with a poor prognosis.

Figure 1. Differential cell cycle control by RB and DREAM

A. RB mediated repression of the activator E2Fs is relieved after cells pass the restriction point. Cyclins D and E in complex with cyclin dependent kinases (CDKs) relieve RB-mediated repression of E2F. The activator E2Fs including E2F1, E2F2 and E2F3 contribute to expression of the early cell cycle genes during the G1 to S phase transition (green arrow). RB may restrict E2F dependent gene expression during DNA damage signalling or oncogene-induced senescence. The classic model of the RB-E2F pathway depicted here does not account for the expression of G2/M late cell cycle genes (blue arrow) during G2/M. Perturbations in RB control of E2F activity occur in most cancer types and include inactivating mutations of the RB gene itself, increased CDK activity due to overexpression of cyclins D and E or loss of FBXW7, decreased expression of CDK inhibitors such as p16^INK4a and p21, or expression of viral cyclins such as KSHV viral cyclin that binds to cellular CDKs and renders them resistant to inhibition by CDK inhibitors ^, . In addition, the viral oncoproteins, papilloma virus E7, polyomavirus large T antigen or adenovirus E1A can bind to RB and dissociate it from E2F. B. The central role of the MuvB core in binding and directing key transcription factors to the promoters of cell cycle genes during various cell cycle phases. MuvB binds p130-E2F4-DP to form DREAM in G0 and repress all cell cycle dependent gene expression. Association of the MuvB core with p130-E2F4 is dependent on DYRK1A-mediated phosphorylation of the MuvB subunit, LIN52. The MuvB core sequentially recruits BMYB during S phase and then FOXM1 to the promoters of the G2/M genes. In all three instances, the MuvB core is essential for targeting the complexes to specific sets of cell cycle gene promoters.

Figure 2. Common themes of repression connect the Muv genes and their homologs

A. Functional antagonism between the MuvB and RAS pathways is evolutionarily conserved. The pathway for development of the vulva in Caenorhabditis elegans is initiated through LIN-3, an epidermal growth factor (EGF)-like ligand. Cells in closer proximity to the anchor cell receive greater amounts of the LIN-3 signal (thick green arrow), and activate a RAS signalling cascade to ultimately acquire a vulval fate (V). Cells farther away receive lesser amounts of the LIN-3 signal (thin green arrows) and develop the hypodermal fate (H). Increased levels of LIN-3 are required to overcome the repressive effects of the synthetic multi-vulval (synMuv) class of genes (A, B and C) on RAS signalling. Notably, homologs of genes in the RB-E2F pathway feature predominantly as class B (MuvB) genes. In Drosophila melanogaster, RB-E2F homologs as well as homologs of several synMuvB genes are required to repress the group E genes, which show sex- and differentiation- specific expression patterns. B. Domains of human MuvB core subunits. Schematic of domains and residue number present in subunits of the MuvB core complex as revealed by Entrez Conserved Domain (CD)-search. The cysteine rich motif domain (CXC) may represent the specific DNA-binding module of LIN54. LIN9 contains a domain in RB-related pathway (DIRP), present in many eukaryotic genomes and its function is unknown. Retinoblastoma binding protein 4 (RBBP4) and its WD40 domain may recruit other proteins or modified histones. C. The amino acid sequence surrounding Serine 28 (S28) residue in LIN52 is highly conserved across several eukaryotic genomes. Domains present in DYRK1A, the kinase responsible for phosphorylating LIN52 at S28 are shown.

Figure 3. Tipping the balance from quiescence to proliferation in cancer

A. Differential regulation of early and late cell cycle gene expression. At least two major peaks of cell cycle gene expression can be discerned during the cell cycle; occurring during G1/S (green line) and G2/M (blue line). The DREAM complex represses both early and late cell cycle gene expression during quiescence (red line). Activator E2Fs (in green) are required for the expression of G1/S genes, while the MuvB core complex, BMYB and FOXM1 (in blue) are required for the expression of G2/M late genes. BMYB and FOXM1 undergo phosphorylation and ubiquitin dependent destruction by the proteasome during S to G2 phase and M to G1 phase transitions, respectively. Repressor E2Fs including E2F6-DP, E2F7 and E2F8 contribute to repression of early or late cell cycle genes, particularly after DNA damage ^{, , -}. B. Loss of DREAM and gain in B-Myb, MuvB and FoxM1 in cancer. Factors over-expressed or amplified (**) or lost (*) in cancers are indicated. The net effect results in loss of DREAM and increased activity of BMYB-MuvB-FOXM1 driving cells out of quiescence and to proliferation.