checkpoint pathways, whose activation leads to a transient cell-cycle arrest and to
programmed cell death (Figure 5). Interestingly, those two DNA damage responses
are spatially separated. Whereas mitotic germ cells halt cell-cycle progression, meiotic
pachytene cells undergo apoptosis (Gartner et al., 2000). Cells outside the germ line
show neither of these responses (Gartner et al., 2000). Like Salmonella-induced germ-
cell death, as well as physiologic germ-cell death, radiation-induced apoptosis appears
to be restricted to the hermaphroditic germ line, requires ced-3 and ced-4, and is also
suppressed by ced-9 loss-of-function mutations (Gartner et al., 2000). In addition,
radiation-induced apoptosis is partially dependent on egl-1 (Gartner et al., 2000).
Consistent with the notion that double strand breaks may cause radiation-induced
programmed cell death, the level of apoptosis is dramatically enhanced in mutants
that are defective in double-strand break repair, such as mre11 and rad-51 (Gartner
et al., 2000; Boulton et al., 2002).
Screens for mutants that are defective in DNA damage-induced apoptosis led to
the discovery of mrt-2, rad-5, and op241 (Figure 5). These mutants are also defective
in cell-cycle arrest and render the worms hypersensitive to DNA damage (Gartner et
al., 2000). mrt-2 was found to be required not only for DNA damage checkpoint but
also for the regulation of telomere replication (Ahmed and Hodgkin, 2000; Gartner
Figure 5. Simplified model of DNA damage checkpoint pathways in fission yeast, C. elegans,
and mammals.
Simplified model of DNA damage checkpoint signaling in various organisms. Note that
apoptosis does not occur in yeasts. Worm p53 affects programmed cell death, but not cell-cycle
arrest It has not been shown whether yeast or mammalian homologs of rad-5 have a function
in DNA damage checkpoint signaling.
174 GENETICS OF APOPTOSIS