E2F1: Cause and Consequence of DNA Replication Stress

Abstract

In mammalian cells, cell cycle entry occurs in response to the correct stimuli and is promoted by the transcriptional activity of E2F family members. E2F proteins regulate the transcription of S phase cyclins and genes required for DNA replication, DNA repair, and apoptosis. The activity of E2F1, the archetypal and most heavily studied E2F family member, is tightly controlled by the DNA damage checkpoints to modulate cell cycle progression and initiate programmed cell death, when required. Altered tumor suppressor and oncogenic signaling pathways often result in direct or indirect interference with E2F1 regulation to ensure higher rates of cell proliferation independently of external cues. Despite a clear link between dysregulated E2F1 activity and cancer progression, literature on the contribution of E2F1 to DNA replication stress phenotypes is somewhat scarce. This review discusses how dysfunctional tumor suppressor and oncogenic signaling pathways promote the disruption of E2F1 transcription and hence of its transcriptional targets, and how such events have the potential to drive DNA replication stress. In addition to the involvement of E2F1 upstream of DNA replication stress, this manuscript also considers the role of E2F1 as a downstream effector of the response to this type of cellular stress. Lastly, the review introduces some reflections on how E2F1 activity is integrated with checkpoint control through post-translational regulation, and proposes an exploitable tumor weakness based on this axis.

Keywords: DNA replication stress; E2F1; cyclin E; cyclin F; retinoblastoma; ribonucleotide reductase; ubiquitin proteasome system.

Figure 1

E2F1: roles as a cause and a consequence of DNA replication stress (“DNA RS” in figure). (A) E2F1 functions upstream and downstream of DNA replication stress. Highlighted in the figure are E2F1-engaging pathways downstream of the DNA RS response when oncogenic and tumor suppressor signaling pathways are intact (light blue), and upstream of DNA RS when oncogenic and/or tumor suppressor signaling pathways are altered (light pink). (B) Consequences of abrogating the E2F1 post-translational regulatory triad comprising Chk1, Rb, and cyclin F. Created with BioRender.com.

Figure 2

DNA replication stress phenotypes resulting from E2F1 dysregulation. Schematic diagram summarizing the different DNA replication stress phenotypes caused by dysregulation of E2F1 and its transcriptional targets cyclin E and RRM2. Phenotypes included above for cyclin E are reported in the literature, while those for RRM2 are hypothesized. Created with BioRender.com.