Biology Reference
In-Depth Information
dNTPs
dNTPs
(B)
(A)
N
Legend
= DNA Lesion
N
N
= Replicative polymerase
= Extender polymerase
= Specialized polymerase
N
N
N
N
N
NNNN
N
NNNN
FIGURE 5.8
Models for the efficient bypass of DNA lesions during translesion DNA synthesis. (A) After encountering a DNA lesion,
a replicative DNA polymerase incorporates a nucleotide opposite it but is unable to extend beyond the lesion. A specialized DNA polymerase
extends beyond the lesion. Once the lesion is bypassed, the specialized polymerase is replaced by the replicative polymerase to resume proc-
essive DNA synthesis. (B) The replicative polymerase stalls at the DNA lesion and is unable to incorporate a nucleotide. In some cases,
a specialized polymerase can incorporate and then extend beyond the DNA lesion prior to being replaced by the replicative enzyme. In other
cases, one specialized polymerase is needed for insertion opposite the lesion and another specialized polymerase is required for extension. (
Please
refer to color plate section
).
DNA polymerase encounters a DNA lesion and incorpo-
rated a nucleotide opposite it. However, the high-fidelity
polymerase is unable to extend beyond the lesion. The
stalling of the replication fork then acts as a signal to
recruit a different DNA polymerase such as pol
k
or
pol
z
that function to extend beyond the lesion. Once
the lesion is by-passed, the replicative DNA polymerase
displaces the extender polymerase to resume processive
DNA synthesis on the remainder of the undamaged
DNA. This scenario likely occurs during the replication
of small miscoding DNA lesions such as O
6
-methylgua-
nine and 8-oxo-guanine.
Model B differs slightly in that as the replicative poly-
merase encounters the lesion, it does not incorporate
a nucleotide. Instead, a specialized polymerase such
as pol
h
is recruited to the lesion and incorporates
a dNTP opposite it. Depending upon the nature of the
lesion, the initial specialized DNA polymerase can also
perform the extension reaction. However, “extender”
polymerases such as pol
z
are typically needed to elon-
gate beyond most bulky DNA lesions. Once the lesion
is by-passed, the replicative DNA polymerase can again
displace the extender polymerase and resume proces-
sive DNA synthesis on the remainder of the undamaged
DNA. This pathway likely functions when crosslinked
or large bulky DNA lesion such as thymine dimers
and cisplatinated DNA are encountered.
As alluded to earlier, the process of lesion by-pass has
historically been viewed as a desperate attempt to
ensure cell survival. As such, this mechanism has been
assumed to cause pro-mutagenic replication that would
further facilitate the formation of genetic errors.
However, the knowledge that many specialized DNA
polymerases actually incorporate the correct coding
nucleotide opposite various DNA lesions cast doubt
on this being an exclusive pro-mutagenic process. While
the details regarding these mechanisms still await final
confirmation, it is clear that the upregulation of certain
specialized DNA polymerases is a common event asso-
ciated with the development of resistance to many types
of DNA damaging agents used in chemotherapy.
For example, pol
h
is capable of extending beyond
cisplatin-DNA lesions, and overexpression of this
specialized DNA polymerases causes resistance to
