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268 CHAPTER 12

2002; Karpowicz et al. 2005). Interestingly, both asymmetric division
and immortal stranding may be regulated by p53 and IMP dehydroge-
nase, the rate-determining enzyme in ribonucleotide biosynthesis (Ram-
bhatla et al. 2005).

STEM CELL SENSITIVITY TO DNA DAMAGE
Mutations in the template strand of a stem cell carry forward through
the stem lineage and the renewing tissue. Cairns (1975) suggested that if
mutagens or other processes caused significant DNA damage to a stem
cell, the cell might undergo apoptosis rather than risk repair. Apopto-
sis would reliably remove the mutations from the tissue. In particular,
Cairns predicted that stem cells would be exceptionally prone to apop-
tosis in response to DNA damage when compared with other cells. Most
other cells have a relatively short expected life for their descendant lin-
eage; for those short-lived cell lineages, DNA damage does not impose
such severe risks as for stem cell lineages.
Several studies suggest that stem cells have extreme sensitivity to
damage, such that even a single radiation-induced hit can trigger apop-
tosis (Potten 1977; Hendry et al. 1982; Potten et al. 1992; Potten and
Grant 1998). Those studies demonstrated sensitivity in gastrointestinal
crypts near where stem cells reside, but it remains difficult to identify
the exact location of stem cells in vivo.
We are left with an association between extreme radiosensitivity of a
small fraction of cells and the expected location of stem cells. Potten
et al. (2002) used the methods described above to label DNA strands
and identify label-retaining cells as stem cells. They then found some
evidence for an association between those cells that retain label and
those cells that undergo apoptosis in response to mild radiation-induced
damage.

TISSUE REPAIR AND RISK OF SYMMETRIC DIVISION
We can measure the age of a DNA strand as the number of strand
replications back to some ancestral template. In Figure 12.10 each “X”
on a strand measures age back to the ancestral template on the left.
If a stem cell dies, it may be replaced by another stem cell (Cairns
2002). The replacement requires a symmetric mitosis, because both
daughters must be retained as stem cells in order to increase by one