Transcriptional control via CDE and CHR promoter elements: signaling proteins in cell cycle regulation

• Applicant: Professor Dr. Kurt Engeland
• Subject Area: Cell Biology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 424870812

Regulation of cell division is essential to prevent cancer development, with transcriptional control serving as a key mechanism in this process. We have discovered a transcription factor binding site, which we named CHR (Cell Cycle Genes Homology Region), that frequently occurs in tandem with the Cell Cycle-Dependent Element (CDE) in the promoters of target genes. Our findings demonstrate that both CDE/CHR tandem sites and single CHR sites are crucial for the cell cycle-dependent expression of over 270 genes involved in cell cycle regulation. This regulation is mediated by the DREAM/MuvB regulatory system. The MuvB core complex associates with proteins from the RB/E2F family of transcription factors to form the DREAM complex, a transcriptional repressor that binds to CHR and CDE/CHR sites and silences genes of cell cycle regulators in quiescent G0 cells. To promote cell cycle progression, a switch occurs from the DREAM repressor complex to activator complexes containing the oncogenic transcription factors A-MYB, B-MYB, and FOXM1, which associate with MuvB to form the A-MYB-MuvB, B-MYB-MuvB, and FOXM1-MuvB complexes, respectively. During this switch, the MuvB core complex remains bound to CHR sites of the target genes, whether within the DREAM repressor complex or within the A-MYB-MuvB, B-MYB-MuvB, and FOXM1-MuvB activator complexes. This switch mechanism enables the transition from repression in G0 to activation from the late G1 phase through mitosis, ensuring precise control over cell cycle-dependent gene expression. Our data have demonstrated that this switch is essential for the appropriate expression of numerous key regulators of cell cycle progression, whose activities drive cells through the cell cycle. Another critical aspect of the DREAM/MuvB regulatory system is its regulation by the tumor suppressor p53. When activated, p53 induces the expression of the p21/CDKN1A CDK inhibitor, which triggers the reverse switch - from the A-MYB-MuvB, B-MYB-MuvB, and FOXM1-MuvB activator complexes back to the DREAM repressor complex. These findings led us to describe the p53-p21-DREAM pathway, which significantly contributes to cell cycle arrest following p53 activation. Our project focuses on investigating previously unrecognized proteins involved in regulating the DREAM/MuvB system and the p53-p21-DREAM pathway. In particular, we will analyze their connection to transcription signals, including epigenetic modifications such as lysine and DNA methylation. We have identified three candidate proteins that our data strongly implicate in interacting with the DREAM/MuvB system and contributing to CHR- and CDE/CHR-dependent regulation. This project will explore how these proteins signal to cooperate with the DREAM/MuvB system to regulate cell division and the p53-p21-DREAM pathway. Our findings will advance the understanding of fundamental biological mechanisms involved in gene and cell cycle regulation and provide new insights into cancer development.

• DFG Programme: Research Grants