The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescence

Abstract

Oncogene-induced senescence is an anti-proliferative stress response program that acts as a fail-safe mechanism to limit oncogenic transformation and is regulated by the retinoblastoma protein (RB) and p53 tumor suppressor pathways. We identify the atypical E2F family member E2F7 as the only E2F transcription factor potently upregulated during oncogene-induced senescence, a setting where it acts in response to p53 as a direct transcriptional target. Once induced, E2F7 binds and represses a series of E2F target genes and cooperates with RB to efficiently promote cell cycle arrest and limit oncogenic transformation. Disruption of RB triggers a further increase in E2F7, which induces a second cell cycle checkpoint that prevents unconstrained cell division despite aberrant DNA replication. Mechanistically, E2F7 compensates for the loss of RB in repressing mitotic E2F target genes. Together, our results identify a causal role for E2F7 in cellular senescence and uncover a novel link between the RB and p53 pathways.

Interaction of E2F7 Transcription Factor with E2F1 and C-terminal-binding Protein (CtBP) Provides a Mechanism for E2F7-dependent Transcription Repression

“…Further, these E2Fs have now been shown to function as repressors of the very genes that are induced by the activator E2Fs (16,17). Such a regulatory relationship has been described as an incoherent feed-forward mechanism in which an activator induces a target but at the same time also induces a repressor of the target, thus limiting the extent of the induction (39).…”

“…ChIP-sequencing analysis reveals that E2F7 binds to multiple G 1 /S-regulated genes and represses their transcription (16). E2F7 is induced by p53 and is involved in cell cycle arrest response to DNA damage and cellular senescence (17)(18)(19). Recent studies using mouse model systems also show that the atypical E2Fs are involved in angiogenesis, polyploidization, and placental development (20 -23).…”

Dual function of C/D box small nucleolar RNAs in rRNA modification and alternative pre-mRNA splicing

“…The correct regulation of the E2F7 alternative exon is likely important for the cell, because use of the exon changes the reading frame and alters the C terminus of the protein, which is necessary for the transcriptional activation of its target genes. E2F7 has antiproliferative properties (61,62), and it is possible that SNORD27 changes observed in cancer influence E2F7-dependent cell cycle regulation.…”

Cell fusion induced by ERVWE1 or measles virus causes cellular senescence

“…A senescent phenotype of the syncytiotrophoblast, including high DCR2 expression, might contribute to this inactivation and thus support the viability of these cells. Of note, knockout of genes that can regulate senescence (pRb or E2F7) leads to disorganization of the trophoblast in mice and even causes embryonic lethality (Narita et al 2003;Wu et al 2003;Aksoy et al 2012;Ouseph et al 2012). Placenta-specific ablation of pRb, for example, causes embryonic lethality, and placenta malfunction is the defect responsible for the embryonic lethality of pRb knockout mice (Wu et al 2003).…”