The CHR promoter element controls cell cycle-dependent gene transcription and binds the DREAM and MMB complexes

Müller, G; Quaas, Marianne; Schümann, Michael; Krause, Eberhard; Padi, Megha; Fischer, Martin; Litovchick, Larisa; DeCaprio, James A.; Engeland, Kurt

doi:10.1093/nar/gkr793

Cited by 95 publications

(213 citation statements)

References 55 publications

(95 reference statements)

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“…Chromatin immunoprecipitation (ChIP) has located DREAM proteins at a majority of E2F and cell cycle homology region (CHR) promoters in human cells, and gene expression analysis has implicated DREAM as a repressor of cell cycle genes (Litovchick et al 2007;Schmit et al 2007;Muller et al 2012). The mechanism of how DREAM regulates transcription has not been elucidated, but it is clear that its central components scaffold a number of key cell cycle transcription factors, including E2F4/ 5, B-Myb, FoxM1, and the Rb tumor suppressor family paralogs p107 and p130 (Korenjak et al 2004;Lewis et al 2004;Litovchick et al 2007;Schmit et al 2007;Sadasivam et al 2012).…”

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Structural mechanisms of DREAM complex assembly and regulation

et al. 2015

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The DREAM complex represses cell cycle genes during quiescence through scaffolding MuvB proteins with E2F4/5 and the Rb tumor suppressor paralog p107 or p130. Upon cell cycle entry, MuvB dissociates from p107/p130 and recruits B-Myb and FoxM1 for up-regulating mitotic gene expression. To understand the biochemical mechanisms underpinning DREAM function and regulation, we investigated the structural basis for DREAM assembly. We identified a sequence in the MuvB component LIN52 that binds directly to the pocket domains of p107 and p130 when phosphorylated on the DYRK1A kinase site S28. A crystal structure of the LIN52-p107 complex reveals that LIN52 uses a suboptimal LxSxExL sequence together with the phosphate at nearby S28 to bind the LxCxE cleft of the pocket domain with high affinity. The structure explains the specificity for p107/p130 over Rb in the DREAM complex and how the complex is disrupted by viral oncoproteins. Based on insights from the structure, we addressed how DREAM is disassembled upon cell cycle entry. We found that p130 and B-Myb can both bind the core MuvB complex simultaneously but that cyclin-dependent kinase phosphorylation of p130 weakens its association. Together, our data inform a novel target interface for studying MuvB and p130 function and the design of inhibitors that prevent tumor escape in quiescence.

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Structural mechanisms of DREAM complex assembly and regulation

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“…The CHR is typically located at or close to the transcriptional start site. Recently, it was shown that the CHR element is bound by the DREAM and MMB transcriptional regulatory complexes, and these complexes play a role in controlling cell cycledependent transcription of genes expressed at the G 2 -M border (10). The DREAM and MMB complexes are functionally interrelated, and both contain the MuvB core complex, which includes LIN9, LIN37, LIN52, LIN54, and RBBP4 in addition to specific additional subunits in each case (11,12).…”

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The Forkhead Transcription Factor FOXM1 Controls Cell Cycle-Dependent Gene Expression through an Atypical Chromatin Binding Mechanism

Chen

Müller

Quaas

et al. 2013

Molecular and Cellular Biology

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bThere are nearly 50 forkhead (FOX) transcription factors encoded in the human genome and, due to sharing a common DNA binding domain, they are all thought to bind to similar DNA sequences. It is therefore unclear how these transcription factors are targeted to specific chromatin regions to elicit specific biological effects. Here, we used chromatin immunoprecipitation followed by sequencing (ChIP-seq) to investigate the genome-wide chromatin binding mechanisms used by the forkhead transcription factor FOXM1. In keeping with its previous association with cell cycle control, we demonstrate that FOXM1 binds and regulates a group of genes which are mainly involved in controlling late cell cycle events in the G 2 and M phases. However, rather than being recruited through canonical RYAAAYA forkhead binding motifs, FOXM1 binding is directed via CHR (cell cycle genes homology region) elements. FOXM1 binds these elements through protein-protein interactions with the MMB transcriptional activator complex. Thus, we have uncovered a novel and unexpected mode of chromatin binding of a FOX transcription factor that allows it to specifically control cell cycle-dependent gene expression. There are nearly 50 different forkhead transcription factors encoded in mammalian genomes, and these proteins all contain the conserved forkhead DNA binding domain (reviewed in references 1 and 2). Forkhead transcription factors are involved in controlling a wide range of biological processes and are aberrantly expressed or regulated in disease states, including cancer (reviewed in reference 2). However, due to sharing a common DNA binding domain, forkhead transcription factors are generally believed to bind to variations of the RYAAAYA motif. Hence, it is unclear how individual forkhead proteins are specifically recruited to the regulatory regions of different cohorts of target genes to control defined biological responses. One key process which is controlled by forkhead transcription factors is the cell cycle and, in particular, the G 2 -M transition. The initial links to G 2 -M control were made with the Saccharomyces cerevisiae forkhead protein Fkh2, which controls the temporal expression of a cluster of genes at this phase of the cell cycle (reviewed in reference 3). More recently, members of the FOXO and FOXM classes of forkhead transcription factors have been linked with controlling the same process in mammalian cells (4-6). In both cases, forkhead transcription factors coordinate the integration of signals from the cell cycle regulatory machinery to transcriptional outputs. This is exemplified by the links to the cell cycle regulated Polo-like kinase PLK1, which is recruited to cell cycle-regulated promoters through promoter elements bound by the forkhead transcription factors FOXM1 and Fkh2, albeit indirectly in the case of Fkh2 (7,8).In mammalian cells, the transcriptional control of a cluster of genes at the G 2 -M transition, is coordinated through promoter elements which typically contain CHR (cell cycle genes homology region) and...

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“…The oncoprotein B-Myb is a key regulator in the switch between transcriptional repression and activation of a large number of genes including PLK1, Aurora A, Cyclin A and Cyclin B1/2 during cell cycle progression through the G2 phase [9][10][11] . B-Myb is part of the transcriptionally activating Myb-MuvB complex, which binds to the CHR promoter elements thereby replacing the DREAM repressor complex 9 .…”

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“…B-Myb is part of the transcriptionally activating Myb-MuvB complex, which binds to the CHR promoter elements thereby replacing the DREAM repressor complex 9 . Interestingly, binding of B-Myb was observed in promoters of many genes controlling the transition from G2 to M phase, and contact to promoter regions appeared to depend on the CHR element, but not on Myb-binding sites 11 .…”

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“…To measure promoter activity with luciferase reporter assays, U2OS cells were plated in 24-well plates (75,000 cells per well) and transfected by lipofection with Fugene 6 (Promega). Cells were cultured overnight, co-transfected with 150 ng of pGL4 promoter reporter plasmids and 25 ng Renilla luciferase control plasmid, collected and assayed as described 9 . In brief, luciferase activity was measured with the dual-luciferase reporter assay system (Promega) following the manufacturer's recommendations.…”

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Cyclin F suppresses B-Myb activity to promote cell cycle checkpoint control

et al. 2015

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Cells respond to DNA damage by activating cell cycle checkpoints to delay proliferation and facilitate DNA repair. Here, to uncover new checkpoint regulators, we perform RNA interference screening targeting genes involved in ubiquitylation processes. We show that the F-box protein cyclin F plays an important role in checkpoint control following ionizing radiation. Cyclin F-depleted cells initiate checkpoint signalling after ionizing radiation, but fail to maintain G2 phase arrest and progress into mitosis prematurely. Importantly, cyclin F suppresses the B-Myb-driven transcriptional programme that promotes accumulation of crucial mitosis-promoting proteins. Cyclin F interacts with B-Myb via the cyclin box domain. This interaction is important to suppress cyclin A-mediated phosphorylation of B-Myb, a key step in B-Myb activation. In summary, we uncover a regulatory mechanism linking the F-box protein cyclin F with suppression of the B-Myb/cyclin A pathway to ensure a DNA damage-induced checkpoint response in G2.

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The CHR promoter element controls cell cycle-dependent gene transcription and binds the DREAM and MMB complexes

Cited by 95 publications

References 55 publications

Structural mechanisms of DREAM complex assembly and regulation

Structural mechanisms of DREAM complex assembly and regulation

The Forkhead Transcription Factor FOXM1 Controls Cell Cycle-Dependent Gene Expression through an Atypical Chromatin Binding Mechanism

Cyclin F suppresses B-Myb activity to promote cell cycle checkpoint control

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