  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 cells
results in CHK1-dependent checkpoint deficiency and multiple mitochondrial
dysfunctions that lead to increased ROS production, energy stress, and
inhibition of de novo pyrimidine synthesis. This deadly 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.
