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also error-prone; typically one to 20 nucleotides can be
lost from each DNA end at NHEJ-mediated rejoining
events (Chapter 8). So, ironically, NHEJ may contribute
to both genome protection and mutation.
Defining a tumor phenotype based on NHEJ has
not been possible to date because severe NHEJ defi-
ciency causes not only profound radiosensitivity and
immune deficiency, but also p53-mediated cell death
(see Chapter 8).
Unexpectedly, higher levels of MRN complex as well
as Ku 70 and DNA-PKcs are predictive of better
response to radiotherapy. While the reasons for this are
yet unknown, speculation is that impaired expression
of the MRN or DNA-PK complexes promotes damage
tolerance, failing to induce cell cycle arrest and
apoptosis (Chapter 8). In this respect, NHEJ is similar
to MMR: intact functionality
significant toxicities that are manifested as neuropathies.
This is particularly prevalent after administration of
platinum agents, microtubule stabilizing drugs, and
ionizing radiation (see Chapter 13). Because the manifes-
tations of these neuropathies (distal paresthesia, altered
proprioception, coldness in extremities, pain, and cogni-
tive impairment/“chemobrain”) are lifestyle-limiting in
many ways, research is attempting to determine how
manipulation of DNA repair can mitigate these treat-
ment side effects.
Several factors noted in Chapter 13 contribute to this
predisposition for primarily sensory neuropathies:
The cell bodies of sensory neurons and many other
nerves outside of the blood
brain barrier are exposed
to higher concentrations of chemotherapeutic drugs
than neurons in the central nervous system.
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not inhibition
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Neurons have high metabolic activity, which makes
them more susceptible to DNA damage.
ensure the efficacy of anticancer treatments.
Because of this, therapeutic forays related to NHEJ
manipulation are taking more of a “sideways” approach
in modulating NHEJ activity. Indirect ways of tweaking
NHEJ functionality may be more fruitful than attempts
at direct inhibition. For example, research shows that
overexpression of a truncated form of XRCC4 inhibits
NHEJ by interfering with DNA ligase IV. Also, binding
of EGFR indirectly modulates NHEJ by suppressing its
nuclear import, which, in turn, suppresses DNA-PK
activity (Chapter 8).
NHEJ modulation may come through more subtle
means as well. Evidence is accumulating that SNPs in
the NHEJ machinery cause increased cancer risk, and
that multiple SNPs such as variant alleles of Ku70 and
80 may have additive or synergistic effects. Epigenetic
factors such as hypermethylation of gene promoters
are under scrutiny as contributing to low levels of
NHEJ repair activity (and thus, predisposition to
cancers) (Chapter 8). How those findings can translate
into future clinical use are yet unknown.
Additional opportunities for influencing NHEJ may
present themselves as researchers learn more about this
rather enigmatic pathway. In the meantime, much more
work remains to be done to understand the mechanisms
behind NHEJ, its interfaces and crosstalk with other
repair pathways (especially HDR and ATM-dependent
signaling), and its influence on chromatin remodeling.
Gene transcription and translation are much higher in
neurons than other types of cells.
A much larger percentage of a person's genomic
DNA is expressed in neurons than in other parts of
the body.
Transcription damage to neuronal DNA, particularly
mitochondrial DNA, causes ensuing functional
damage to neurons.
Research is underway to determine how altering the
expression of certain DNA repair proteins (specifi-
cally, APE1) can prevent or minimize issues related
to peripheral neuropathies. Enhancing DNA repair
mechanisms selectively to neurons is a novel target
for improving patient outcomes, particularly quality
of life. A strong body of evidence shows that the
repair component of APE1 can attenuate neurotoxic-
ities, but the challenge is to determine how to spare
neurons without “feeding” the repair abilities of
cancer cells.
ROADMAP FOR FUTURE
DEVELOPMENTS
One can say that the future for DNA repair inhibitors
is only beginning.
8
But, to effectively tackle the tenacity
of cancer with DNA repair inhibitors and other types of
inhibitors, a comprehensive approach to R&D and
patient care must occur. This can be described as nine
“buckets” of activities.
NEUROPROTECTION AND TARGETED
THERAPY
Molecular characterization of DNA repair and the
proteins influencing it are central to yet another
emerging clinical application: protection from neuropa-
thies induced by anticancer treatments. Oxidative stress
and/or direct damage to neuronal DNA causes
1. Continue to More Fully Characterize
DNA Repair Pathways on the Molecular Level
Much is yet to be learned about DNA repair path-
ways. For example, controversy still exists regarding
