Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

264 Chapter 5: DNA Replication, Repair, and Recombination
3′ overhang
5′
3′
telomere
repeats
5′
3′
5′
3′
t-loop
5′
3′
(A)
1 µm
(B)
strand exchange by 3′ overhang
Telomere Length Is Regulated by Cells and Organisms
Because the processes that grow and shrink each telomere sequence are only
approximately balanced, a chromosome end contains a variable number of telomeric
repeats. Not surprisingly, many cells have homeostatic mechanisms that
maintain the number of these repeats within a limited range (Figure 5–36).
In most of the dividing somatic cells of humans, however, telomeres gradually
MBoC6 m5.42/5.36
shorten, and it has been proposed that this provides a counting mechanism that
helps prevent the unlimited proliferation of wayward cells in adult tissues. In its
simplest form, this idea holds that our somatic cells start off in the embryo with a
full complement of telomeric repeats. These are then eroded to different extents in
different cell types. Some stem cells, notably those in tissues that must be replenished
at a high rate throughout life—bone marrow or gut lining, for example—
retain full telomerase activity. However, in many other types of cells, the level of
telomerase is turned down so that the enzyme cannot quite keep up with chromosome
duplication. Such cells lose 100–200 nucleotides from each telomere every
time they divide. After many cell generations, the descendant cells will inherit
chromosomes that lack telomere function, and, as a result of this defect, activate
a DNA-damage response causing them to withdraw permanently from the cell
cycle and cease dividing—a process called replicative cell senescence (discussed
in Chapter 17). In theory, such a mechanism could provide a safeguard against
the uncontrolled cell proliferation of abnormal cells in somatic tissues, thereby
helping to protect us from cancer.
Figure 5–35 A t-loop at the end of a
mammalian chromosome. (A) Electron
micrograph of the DNA at the end of an
interphase human chromosome. The
chromosome was fixed, deproteinated, and
artificially thickened before viewing. The
loop seen here is approximately 15,000
nucleotide pairs in length. (B) Structure
of a t-loop. The insertion of the singlestrand
3ʹ end into the duplex repeats is
carried out, and the structure maintained,
by specialized proteins. (From J.D. Griffith
et al., Cell 97:503–514, 1999. With
permission from Elsevier.)
chromosome end
5′
3′
long telomere
telomere repeats
5′
3′
5′
3′
short
telomere
5′
3′
fraction of chromosome ends
increasing telomere length
INCREASING NUMBER OF CELL DIVISIONS
increasing telomere length
Figure 5–36 A demonstration that
yeast cells control the length of their
telomeres. In this experiment, the telomere
at one end of a particular chromosome
is artificially made either longer (left) or
shorter (right) than average. After many
cell divisions, the chromosome recovers,
showing an average telomere length and
a length distribution that is typical of the
other chromosomes in the yeast cell. A
similar feedback mechanism for controlling
telomere length has been proposed for the
germ-line cells of animals.