Page 281 - 20dynamics of cancer

266 CHAPTER 12

x x x
(a) x x x x x x x
x x x x

(b) x x x x x x x x
x
x
x x x x x x
x x x x x x x x xx

Figure 12.10 Cairns’ (1975) hypothesis of asymmetric DNA segregation in stem
cell divisions. (a) Immortal stranding, in which the stem lineage along the bot-
tom always receives the older strand of the DNA duplex in each round of cell
division. (b) Segregation of the newer DNA strand to the stem cell lineage in each
round of cell division. Random segregation would follow a stochastic process
between these two patterns. See text for full discussion.

IMMORTAL STRANDING

In every mitosis, the DNA duplex splits, each strand acting as a tem-
plate for replication to produce a new complementary strand. It is pos-
sible that most mutations during replication arise on the newly syn-
thesized strand. A stem lineage could reduce its mutation rate if each
stem cell division segregated the oldest template strands to the daugh-
ter destined to remain in the stem lineage and the newer strands to the
daughter destined for the short-lived transit lineage.
Figure 12.10a shows Cairns’ hypothesis for segregation of DNA tem-
plate strands. The DNA duplex at the lower left begins with identical
DNA strands. The duplex splits as shown, and each strand serves as a
template for replication. Suppose, each time a stem cell copies its DNA,
that during replication one new mutation arises on the new strand. The
“X” marks the new mutation. In the figure, the first round of replication
shows the original templates without mutations and the newly repli-
cated strands, each new strand with one mutation.
With each subsequent round of replication in Figure 12.10a, the older
template without mutations segregates to the stem lineage along the
bottom, and the younger strand with one new mutation segregates up
to the transit lineage. This pattern reaches a steady state, in which the
stem line retains the original template strand and a strand replicated