Biology Reference
In-Depth Information
phosphorylation of threonine 233 residue operated by
Cdk5 has been demonstrated to occur
in vivo
.
170
Ubiqui-
tin is a highly conserved 76 amino acid protein which
serves as signal mediator of a number of cellular activi-
ties, including cell cycle and DNA repair, with links to
cancer upon dysregulation.
171
Poly-ubiquitination of
a protein triggers its degradation through the 26S pro-
teasome,
172
while ubiquitin is removed by a deubiquiti-
nase (DUB) or a ubiquitin-specific protease (USP).
173
Mono-ubiquitinated proteins can stably exist, and the
target protein may have modifications in activity, subcel-
lular localization, and protein/DNA interaction. Mecha-
nism of APE1 ubiquitination was recently characterized
by Busso and colleagues
174
as being regulated by p53
and catalyzed by MDM2, and possibly increasing
APE1 stability and affinity for DNA.
166
S-nitrosation of
cysteine 93 and 310, induced by S-nitrosoglutathione,
was reported to trigger APE1 exclusion from nuclei,
providing a new mechanism of APE1 nuclear export.
175
The proteolytic cleavage of the N-terminal portion of
APE1 is a peculiar and irreversible PTM, which appears
extremely intriguing and not yet well understood.
Formation of truncated N
D
33-APE1 protein was
reported in natural killer cells to be operated by Gran-
zyme A (GzmA) in a caspase-independent cell death
pathway, leading to the inhibition of APE1 repair
activity.
176
However, it is known from other studies
that loss of N-terminal portion does not inhibit APE1
endonuclease activity.
167
Truncated APE1 protein was
detected in the cytoplasm of some cell types, and
because of the loss of the NLS, this modification was
suggested to be responsible for APE1 targeting within
the mitochondria.
177
However, at least in some cell
types, the prevalent mitochondrial form of APE1 is the
full length
66
(also Vascotto
et al.
, unpublished data),
thus indicating that APE1 internalization into the mito-
chondria follows another mechanism, as recently sug-
gested.
178
Clearly, the N-terminal portion of APE1 is
directly involved in protein/protein interaction and in
the binding to RNA molecules.
76
Unfortunately, many
unresolved questions remain concerning the identifica-
tion of the protease, the determination of the stimuli
capable of inducing such PTM, the analysis of the
cellular compartment where this modification takes
place, and the effects of the modification on the sub-
cellular localization and the activities of truncated APE1.
the decision for DNA repair, cell cycle arrest, or cell
death is evaluated. Manipulation of the processing of
base damage by these pathways has the potential to shift
the balance from repair to apoptosis or cell death,
a favorable outcome in tumor cells. Many chemothera-
peutic agents kill cancer cells by damaging their DNA,
therefore inhibiting the action of BER in cancer cells
could render them more sensitive to these agents.
Several chemotherapeutic agents generate lesions that
BER would repair, including temozolomide (TMZ),
melphalan, thiotepa, methyl-lexitropsin (Me-lex),
dacarbazine/procarbazine, and streptozotocin.
3
More
recently, it has become clear that some chemotherapeutic
agents generate reactive oxygen species (ROS)
secondary to their primary mechanism of action. BER
proteins are the predominant mechanism to rid cells
of oxidative DNA damage. Chemotherapeutics such as
platinum-based drugs,
179-180
anthracyclines, i.e. epirubi-
cin, daunorubicin, doxorubicin,
181
and paclitaxel
182
e
183
generate ROS, indicating that BER may play a role in
cellular response to these drugs even though they have
not been considered to generate single base lesions.
Another frequent treatment modality in cancer is
ionizing radiation (IR) and BER is one of the DNA repair
pathways that contributes to the repair of the DNA
damage generated.
184
Due to the DNA damage generated by agents such as
TMZ and IR, rational combinations of IR/alkylating
agents and BER inhibitors have been described and are
ongoing both preclinically and in clinical trials.
2
e
3
Strat-
egies involving synthetic lethality of tumor survival may
offer the most promise for clinical utility against the
dreaded disease of cancer. This is the notion that the
pairing of two hits is sufficient to kill cancer cells and
can markedly improve the efficacy of single-target
agents.
185
e
186
For example, the blockade of PARP in
BRCA-deficient tumor cells renders them dramatically
more sensitive to PARP inhibitors than BRCA-proficient
cells (
Figure 3.5
).
2,187
Cancer cells are genetically
unstable and frequently lose tumor suppressor genes
and inactivate DNA repair pathways as they progress
to a fully malignant state. Yet, upregulation of DNA
repair gene expression has also been implicated in
drug resistance and poor prognosis, leaving cancer cells
“addicted” to their functions and able to evade chemo-
or radiotherapy. In the case of PARP inhibition and
BRCA deficiency, the blockade of BER via PARP inhibi-
tors inactivates another pathway of DNA repair in these
HR-deficient cells resulting in hypersensitivity.
187-188
Another potential benefit of this type of therapy is selec-
tivity for therapeutic benefit in the tumor tissue instead
of the normal tissues where DNA repair mechanisms are
intact. PARP inhibitors are showing clinical benefit in
several types of cancers and provide proof-of-concept
that inhibition of DNA repair, and more specifically
BER PROTEINS AS TARGETS
IN CANCER TREATMENT
Both short- and long-patch BER pathways contribute
to the maintenance of genomic integrity in cells.
A balance exists in which the endogenous and exoge-
nous damage that a cell encounters is processed and
