Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM

Abstract

Activation of the p53 tumor suppressor can lead to cell cycle arrest. The key mechanism of p53-mediated arrest is transcriptional downregulation of many cell cycle genes. In recent years it has become evident that p53-dependent repression is controlled by the p53-p21-DREAM-E2F/CHR pathway (p53-DREAM pathway). DREAM is a transcriptional repressor that binds to E2F or CHR promoter sites. Gene regulation and deregulation by DREAM shares many mechanistic characteristics with the retinoblastoma pRB tumor suppressor that acts through E2F elements. However, because of its binding to E2F and CHR elements, DREAM regulates a larger set of target genes leading to regulatory functions distinct from pRB/E2F. The p53-DREAM pathway controls more than 250 mostly cell cycle-associated genes. The functional spectrum of these pathway targets spans from the G₁ phase to the end of mitosis. Consequently, through downregulating the expression of gene products which are essential for progression through the cell cycle, the p53-DREAM pathway participates in the control of all checkpoints from DNA synthesis to cytokinesis including G₁/S, G₂/M and spindle assembly checkpoints. Therefore, defects in the p53-DREAM pathway contribute to a general loss of checkpoint control. Furthermore, deregulation of DREAM target genes promotes chromosomal instability and aneuploidy of cancer cells. Also, DREAM regulation is abrogated by the human papilloma virus HPV E7 protein linking the p53-DREAM pathway to carcinogenesis by HPV. Another feature of the pathway is that it downregulates many genes involved in DNA repair and telomere maintenance as well as Fanconi anemia. Importantly, when DREAM function is lost, CDK inhibitor drugs employed in cancer treatment such as Palbociclib, Abemaciclib and Ribociclib can compensate for defects in early steps in the pathway upstream from cyclin/CDK complexes. In summary, the p53-p21-DREAM-E2F/CHR pathway controls a plethora of cell cycle genes, can contribute to cell cycle arrest and is a target for cancer therapy.

Figure 1

Cell cycle and transcription factor complexes. The protein complexes binding to DNA change during the cell cycle. Gene expression is repressed in the early phases of the cell cycle and becomes activated during the later phases. For this change, E2F and CHR (cell cycle genes homology region) promoter elements switch from repressor to activator sites. In G₀ and early G₁ phase the DREAM complex binds E2F, CHR, CDE (cell cycle-dependent element), and CLE (CHR-like element) sites to repress transcription. In G₂ phase and mitosis transcriptional repression is released and activation occurs via CHR sites. Only promoters with CHR sites can bind the MuvB-based complexes MMB (B-MYB-MuvB), FOXM1-MMB and FOXM1-MuvB. The MuvB core complex is composed of LIN9, LIN37, LIN52, LIN54 and RBBP4 proteins. LIN54 is the component which binds to CHR elements. For the switch from repressing to activating complexes, B-MYB and FOXM1 are recruited to the MuvB core when E2F4-5/DP and p107/p130 dissociate from the complex. B-MYB-MuvB (MMB), FOXM1-MMB and FOXM1-MuvB complexes serve as activators of late cell cycle genes which carry functional CHR elements. Early cell cycle genes with maximum expression in the S phase are activated by E2F1-3/DP heterodimers through E2F sites

Figure 2

Modes of DREAM binding. DREAM can form two distinct contacts with DNA. It can bind to DNA via single E2F (a) or CHR (b) sites. E2F sites are contacted through E2F4-5/DP heterodimers. Distinct from this binding, contacts to CHR elements are made via the LIN54 protein. In the figure, the LIN54 component of the MuvB core complex is the only constituent that is labeled. Binding to E2F or CHR elements can be supported by CLE (c) or CDE (d) sites, respectively. CDE and CLE sites differ from E2F and CHR elements as CDE and CLE sites are unable to bind DREAM as single elements

Figure 3

The p53–p21–DREAM–E2F/CHR pathway. Indirect p53-dependent repression through DREAM. Induction of p53 leads to downregulation of genes. This regulation is indirect as p53 does not bind to the regulated genes. Instead, induction of p21/CDKN1A expression by p53 causes hypophosphorylation of p107 and p130. Hypophosphorylation of these pRB-related pocket proteins facilitates DREAM formation. DREAM complexes then displace the activating complexes FOXM1–B-MYB-MuvB (FOXM1-MMB) and E2F1-3/DP on the target promoters. (In the figure, LIN54 is the only labeled MuvB component.) Overall, this switch causes previously activated genes to be indirectly downregulation by p53

Figure 4

Cellular functions of the p53–p21–DREAM–E2F/CHR pathway. In order to summarize cellular functions regulated by the pathway, gene ontology terms for p53–p21–DREAM–E2F/CHR targets from Table 1 were compiled