DNA‐damage response control of E2F7 and E2F8

Abstract

Here, we report that the two recently identified E2F subunits, E2F7 and E2F8, are induced in cells treated with DNA-damaging agents where they have an important role in dictating the outcome of the DNA-damage response. The DNA-damagedependent induction coincides with the binding of E2F7 and E2F8 to the promoters of certain E2F-responsive genes, most notably that of the E2F1 gene, in which E2F7 and E2F8 coexist in a DNA-binding complex. As a consequence, E2F7 and E2F8 repress E2F target genes, such as E2F1, and reducing the level of each subunit results in an increase in E2F1 expression and activity. Importantly, depletion of either E2F7 or E2F8 prevents the cell-cycle effects that occur in response to DNA damage. Thus, E2F7 and E2F8 act upstream of E2F1, and influence the ability of cells to undergo a DNA-damage response. E2F7 and E2F8, therefore, underpin the DNA-damage response.

Atypical E2F activity restrains APC/C CCS52A2 function obligatory for endocycle onset

“…Whether E2F7 controls the timing of cell cycle exit in this manner remains to be demonstrated. Significantly, in contrast to mammalian cells that undergo widespread apoptosis in the absence of E2F7 and E2F8 (20,21), the del1-1 lines display no signs of cell death. Treatments that cause apoptosis in mammals, such as E2F overexpression or exposure to genotoxic compounds, provoke endoreduplication rather than cell death in Arabidopsis (37,38), suggesting that apoptosis and endoreduplication might represent evolutionarily equivalent response mechanisms in mammals and plants to cope with potentially harmful cells.…”

“…To investigate whether the observed control of the APC/C activator genes by atypical E2F proteins might be conserved among plants and metazoans, we evaluated the binding of the human E2F7 transcription factor to the CDH1 promoter by ChIP analysis in human bone tissue-derived osteosarcoma cells (U2OS). As a positive control, we tested the association of E2F7 with the E2F1 gene, recently demonstrated to be an E2F7 target gene (20,21). No E2F1 or CDH1 promoter DNA was precipitated with a nonspecific antibody, but both promoters could be detected in the E2F7 immunoprecipitates (Fig.…”

“…In contrast to the classical E2F proteins, the physiological relevance of the novel E2Fs is less clear. E2F7 and E2F8 have been demonstrated to play a role in controlling E2F1-dependent apoptosis (20,21), whereas in plants, atypical E2Fs operate as inhibitors of postmitotic events; mutants of E2Fe/DEL1 display increased endoreduplication levels (22), whereas E2Ff/DEL3-deficient plants are prone to rapid cell expansion (23).…”

Involvement of atypical transcription factor E2F8 in the polyploidization during mouse and human decidualization

“…During cell cycle transition, E2F7 and E2F8 should restrain E2F1 activity throughout the S and G2 phases, otherwise the cells may favor E2F1 induced apoptosis; Except cell cycle regulation, E2F7 and E2F8 were induced in cells treated with DNA-damaging agents, transcriptionally repressing E2F1 expression and inhibiting E2F1-dependent apoptosis. 19 Mice that are doubly deficient for E2F7 and E2F8 failed to survive on E11.5, displaying widespread apoptosis without defects in proliferation, and the high level of E2F1 and p53, while inhibiting p53 and E2F1 could rescue cell apoptosis. 20 Taken together, these results demonstrate E2F8 mediated polyploidy status could increase the cellular resistance to stresses and endow the decidual cells with pro-survival strategies by inhibiting pro-apoptotic pathways.…”

“…14,15 Several studies have associated atypical E2Fs in cell proliferation, differentiation and apoptosis, embryo development, angiogenesis, polyploidization of hepatocytes and trophoblast giant cells (TGC) and tumorigenesis. 7,9,[16][17][18][19][20][21][22][23] However, the expression, regulation and function of atypical E2Fs in mouse uterus during early pregnancy are still unknown.…”