Timing of transcription during the cell cycle: Protein complexes binding to E2F, E2F/CLE, CDE/CHR, or CHR promoter elements define early and late cell cycle gene expression.

Gerd A Müller,Axel Wintsche,Konstanze Stangner,Kurt Engeland,Thomas Schmitt

doi:10.18632/oncotarget.10888

Abstract

A central question in cell cycle control is how differential gene expression is regulated. Timing of expression is important for correct progression through the cell cycle. E2F, CDE, and CHR promoter sites have been linked to transcriptional repression in resting cells and activation during the cell cycle. Further, the DREAM complex binds CHR or CDE/CHR elements of G2/M genes resulting in repression during G0/G1. Here, we show that DREAM also binds to E2F sites of S phase genes in quiescence and upon p53 activation. Furthermore, we describe a novel class of promoter sites, the CHR-like elements (CLE), which can support binding of DREAM to E2F elements. Activation of such S phase genes is achieved through binding of E2F1-3/DP complexes to E2F sites. In contrast, the activating MuvB complexes MMB and FOXM1-MuvB bind to CHR elements and mediate peak expression in G2/M. In conclusion, data presented here in combination with earlier results leads us to propose a model that explains how DREAM can repress early cell cycle genes through E2F or E2F/CLE sites and late genes through CHR or CDE/CHR elements. Also p53-dependent indirect transcriptional repression through the p53-p21-Cyclin/CDK-DREAM-E2F/CLE/CDE/CHR pathway requires DREAM binding to E2F or E2F/CLE sites in early cell cycle genes and binding of DREAM to CHR or CDE/CHR elements of late cell cycle genes. Specific timing of activation is achieved through binding of E2F1-3/DP to E2F sites and MMB or FOXM1-MuvB complexes to CHR elements.

Highlights

Cell cycle-dependent transcriptional regulation is a hallmark of the cell division cycle [1]
We provide evidence that DREAM binds to E2F elements in the promoters of S phase genes and that downstream CHRlike elements (CLE) can support the interaction, while binding to promoters of late cell cycle genes depends on CHR sites that can be supported by CDEs (Table 1)
The observation that CLEs contribute to p53-dependent transcriptional repression, together with the results described above that DREAM binding is supported by CLEs but not binding of E2F1-3/pRB (Figure 4), implies that the response of these genes to p53 is mediated rather by DREAM than by E2F1-3/pRB complexes

Summary

Introduction

Cell cycle-dependent transcriptional regulation is a hallmark of the cell division cycle [1]. We have recently shown that DREAM binds to CHR elements or CDE/CHR tandem sites of late cell cycle gene promoters in non-proliferating cells or upon activation of p53 [5,6,7,8,9,10]. In these cases, the complex predominantly binds to CHR elements. The complex predominantly binds to CHR elements This was shown by mutation of CHR sites, which led to a complete loss of DREAM binding despite presence of CDE sites. LIN54 has been shown to bind to CHR sites in vitro [11], and E2F4/DP1 interact with E2F binding sites [12, 13]

Methods

Results

Conclusion