Abstract
Recent data support the notion that a group of key transcriptional regulators involved in tumorigenesis, including MYC, p53, E2F1, and BMI1, share an intriguing capacity to simultaneously regulate metabolism and cell cycle. Here, we show that another factor, the multifunctional protein E4F1, directly controls genes involved in mitochondria functions and cell-cycle checkpoints, including Chek1, a major component of the DNA damage response. Coordination of these cellular functions by E4F1 appears essential for the survival of p53-deficient transformed cells. Acute inactivation of E4F1 in these cellsresults in CHK1-dependent checkpoint deficiency and multiple mitochondrial dysfunctions that leadto increased ROS production, energy stress, andinhibition of de novo pyrimidine synthesis. Thisdeadly cocktail leads to the accumulation of uncompensated oxidative damage to proteins and extensive DNA damage, ending in cell death. This supports the rationale of therapeutic strategies simultaneously targeting mitochondria and CHK1 for selective killing of p53-deficient cancer cells.
Highlights
RESULTSE4F1 transcription factor was found to regulate the viral E4 and E1A promoters (Lee and Green, 1987; Fernandes and Rooney, 1997), but its cellular target genes remain largely unknown
As previous reports showed that the CHK1-dependent checkpoint is important for the survival of p53-deficient cancer cells exposed to DNA-damaging agents inducing replicative stress (McNeely et al, 2014), we evaluated the sensitivity of p53-deficient E4F1KO transformed mouse embryonic fibroblasts (MEFs) to hydroxyurea (HU)
Consistent with a role of E4F1 in the basal expression of CHK1, E4F1KO transformed cells treated with HU only exhibited a profile indicative of a compromised arrest in S and G2/M and of enhanced cell death (Sub-G1) that was similar to that of control cells treated with both HU and the CHK1 inhibitor (Figure 5F)
Summary
Rodier et al show that the transcription factor E4F1, previously described as a regulator of the p53 response and a target of E1A, directly controls a transcriptional program involved in mitochondrial homeostasis, metabolism, and cell-cycle checkpoints. This program is essential for cancer cell survival. Highlights d Transcriptional target genes of E4F1 encode mitochondrial and checkpoint proteins. The Transcription Factor E4F1 Coordinates CHK1-Dependent Checkpoint and Mitochondrial Functions
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