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

274 Chapter 5: DNA Replication, Repair, and Recombination
5′
3′
sliding clamp
covalent modifications
to sliding clamp when
polymerase encounters
DNA damage
DNA damage
replicative DNA
polymerase released
Figure 5–44 Translesion DNA
polymerases can use damaged
templates. According to this model, a
replicative polymerase stalled at a site of
DNA damage is recognized by the cell
as needing rescue. Specialized enzymes
covalently modify the sliding clamp
(typically, it is ubiquitylated—see Figure
3–69) which releases the replicative DNA
polymerase and, together with damaged
DNA, attracts a translesion polymerase
specific to that type of damage. Once the
damaged DNA is bypassed, the covalent
modification of the clamp is removed, the
translesion polymerase dissociates, and
the replicative polymerase is brought back
into play.
loading of translesion polymerase
by assembly factors
translesion DNA
polymerase
DNA synthesis
removal of covalent modifications, reloading of replicative
DNA polymerase, DNA synthesis continues
repair. Ionizing radiation, replication errors, oxidizing agents, and other metabolites
produced in the cell cause breaks of this type. If these lesions were left unrepaired,
they would quickly lead to the breakdown of chromosomes into smaller
MBoC6 n5.100/5.45
fragments and to loss of genes when the cell divides. However, two distinct mechanisms
have evolved to deal with this type of damage (Figure 5–45). The simplest to
understand is nonhomologous end joining, in which the broken ends are simply
brought together and rejoined by DNA ligation, generally with the loss of nucleotides
at the site of joining (Figure 5–46). This end-joining mechanism, which can
be seen as a “quick and dirty” solution to the repair of double-strand breaks, is
common in mammalian somatic cells. Although a change in the DNA sequence
(a mutation) results at the site of breakage, so little of the mammalian genome is
essential for life that this mechanism is apparently an acceptable solution to the
problem of rejoining broken chromosomes. By the time a human reaches the age
of 70, the typical somatic cell contains over 2000 such “scars,” distributed throughout
its genome, representing places where DNA has been inaccurately repaired by
nonhomologous end joining. But nonhomologous end joining presents another
danger: because there seems to be no mechanism to ensure that two ends being
joined were originally next to each other in the genome, nonhomologous end
joining can occasionally generate rearrangements in which one broken chromosome
becomes covalently attached to another. This can result in chromosomes
with two centromeres and chromosomes lacking centromeres altogether; both