Biology Reference
In-Depth Information
With very few exceptions, neither approach met
real-world expectations. Scientists observed indirectly,
then learned empirically, that (1) cancers are more
heterogeneous than bacterial targets, (2) genes govern
a plethora of functions that collectively contribute to
carcinogenic transformation, and (3) cells have
numerous built-in mechanisms of DNA damage repair
that thwart chemotherapeutic efficacy. In attempts to
overcome intrinsic or acquired treatment resistance,
many combinations of treatments have been and are
being tried.
As scientists looked for unique features of cancers to
target for treatment, the biggest treatment conundrum
reared its head: how to kill cancer cells without causing
similar damage to normal cells. Developing more tar-
geted chemotherapeutics and better delivery methods
has remained paramount as new treatments go from
bench to bedside. Only in recent years have scientists
started to tap into their knowledge of DNA repair path-
ways as a means for solving this ominous problem. The
study of rare genetic diseases paved the way for this
new paradigm.
The critical role of DNA repair in preventing cancer
in humans first came to light in studying individuals
with xeroderma pigmentosum (XP), a rare recessive
genetic disorder characterized by the inability to repair
DNA damage caused by ultraviolet light. This defi-
ciency leads to premature aging and multiple forms
of skin cancer. Investigation of XP's underlying causes
revealed a mutation in an enzyme in the nucleotide
excision repair pathway (NER) of people with XP;
this defect reduces or eliminates one or both sub-
pathways of NER activity. 5,6 Since then, scientists have
uncovered a handful of other hereditary conditions
including Fanconi anemia and certain cancers (non-
polyposis colon cancer, familial breast and ovarian
cancers) that are constitutively deficient in a particular
DNA repair pathway. 2,7
Studies on aging have provided additional under-
standing of DNA repair processes. DNA damage
does not always lead to mutagenesis. The body can
eliminate cells with low-level DNA damage; this
protects the body from cancer but at the expense of
accelerating aging. An extreme example of this is Cock-
ayne's syndrome, which causes severe progeroid
syndromes. 5 Mutations in the genes that encode two
proteins in a NER sub-pathway called transcription
coupled repair (TCR) cause global premature cell
death. And, although premature aging is a hallmark
of this disease, no person with Cockayne's syndrome
has ever been documented as developing cancer. 5
This underscores the relationship between DNA
damage, cancer, and aging e and sheds light on the
arsenal of options that cells have for preserving
genome integrity.
In addition, DNA damage can initiate cancer, but cells
may also induce DNA injury to protect against cancer.
This is seen in the loss of protective telomeric repeats
at chromosome ends. Precancerous cells have critically
short telomeres that behave like DSBs in that they
awaken the DNA damage-response system, triggering
cell-cycle arrest and death. This shows what extent the
body will go to in order to protect genome integrity,
and it highlights one of the maladaptive processes that
almost all tumors exhibit. Approximately 90% of all
cancers possess reactivated telomerase to overcome
this natural barrier to growth. 5
Thus, DNA damage can elicit one of four cellular
responses: repair, senescence, death, or mutation. The
decisions that lead to one response or another are
governed by multiple repair pathways and various
replication apparatuses including checkpoints, signal-
transduction and effector systems, all of which influence
transcription, recombination, chromatin remodeling
and differentiation. The fact that DNA's integrity nor-
mally remains intact is remarkable when one considers
that
DNA is the only biologic molecule that relies solely on
its “survival” and the integrity of its information by
repairing existing molecules instead of synthesizing
new ones.
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DNA accumulates damage from both endogenous
and exogenous sources over its lifetime.
￿
Most cells contain only one copy of its information.
￿
DNA undergoes approximately 10 4 spontaneous base
losses and single-strand breaks (SSBs) per day per
cell. 5
DNA's stability is assaulted from three sides. 5,8
Hydrolysis and other spontaneous intracellular reac-
tions can create abasic sites and cause deamination.
Cellular metabolism generates reactive oxygen and
nitrogen species that can cause SSBs as well as
numerous oxidative base and sugar products. In addi-
tion, lipid peroxidation products, carbonyl species,
endogenous alkylating agents, and estrogen and choles-
terol metabolites cause other types of DNA damage.
Exogenous physical and chemical agents, naturally
occurring and synthetically made (such as chemothera-
peutics), cause many types of DNA damage. 5
Given the complexity of DNA damage response
and repair, it is a virtual certainty that part of its
machinery goes awry in cancers. Similar to when
bad data is resaved to a hard drive, mutagenic DNA
information becomes more garbled, fragmented, and
transformed with subsequent “saves.” Recent studies
provide evidence that defective DNA damage repair
is present in virtually all tumors, 5 but scientists are
just starting to exploit that clinically to its greatest
advantage.
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