Genetics of Apoptosis

to apoptosis, indicating that E4orf4-induced events in yeast and mammalian cells are
highly conserved.
In mammalian cells, inhibition of proteasome-dependent proteolysis leads to either
induction or repression of apoptosis, depending on the proliferative status of the cells.
It has been suggested that in exponentially growing cells, proteasomes continuously
degrade an activator of apoptosis (Drexler, 1997). To characterize which role the
proteasome plays in yeast apoptosis, Ligr et al. (2001) screened for proteasomal
substrates and found six genes which by overexpression in a proteasome-deficient
background trigger apoptosis. One of the genes, SAR1, is required for vesicular
transport from ER to Golgi; hence, it is involved in a similar process as CDC48.
Another gene is STM1, a DNA-binding protein involved in DNA repair. STM1
knockout strains show enhanced resistance to oxygen stress. Ligr suggests that STM1
protein is an activator of apoptosis triggered by exposure of cells to low concentrations
of H 2 O 2.
Another form of external stress resulting in apoptosis has been described by
Ludovico et al. (2001). After treatment with low doses of acetic acid, yeast dies,
showing markers of apoptosis. Again, this is accompanied by formation of ROS (our
unpublished data).

5.

DNA damage induces yeast apoptosis

Recently, the first evidence was reported that an apoptotic phenotype in yeast can be
induced by DNA damage after UV irradiation, as monitored with the TUNEL test.
Interestingly, a UV dose-dependent increase in the sub-G1 population was found by
flow cytometry. Sub-G1 cells were isolated by flow sorting and analyzed by electron
microscopy. This population showed condensed chromatin in the nucleus and cell
shrinking (Carratore et al., 2002).
Cytolethal distending toxins (CDTs) are multisubunit proteins produced by a
variety of bacterial pathogens that cause cell-cycle arrest and apoptosis in mammalian
cells. Recent studies suggest that they can act as intracellular DNases in mammalian
cells. Expression of a CdtB subunit in yeast causes a G 2 /M arrest, as seen in
mammalian cells. CdtB toxicity is not circumvented in yeast genetically altered to
lack DNA damage checkpoint control or that constitutively promotes cell cycle
progression via mutant Cdk1, because CdtB causes a permanent type of damage that
results in loss of viability (Hassane et al., 2001).

6.

Speculations about the origin of apoptosis

The importance of ROS in the regulation of apoptosis may indicate the origin and
primary purpose of the suicide process. ROS are byproducts of respiration and occur
in every aerobic organism. Because ROS are highly reactive and modify proteins,
lipids, and nucleic acids, ROS-induced cell damage is a common and efficient event.

146 GENETICS OF APOPTOSIS