[ RadSafe ] Article: DNA Damage Responses: Cancer and Beyond

John Jacobus crispy_bird at yahoo.com
Thu Oct 13 15:33:16 CDT 2005

This appeared in The Scientist at 

Volume 19 | Issue 19 | Page 24 | Oct. 10, 2005

DNA Damage Responses: Cancer and Beyond
Have we learned enough to design new therapies or
prevention approaches?
By Michael B. Kastan

The composition and sequence of 3 billion bases of DNA
serve as a major determinant of our individual
physiology. Unfortunately, our DNA is constantly being
challenged by agents that arise from either normal
metabolism or exposures to natural or artificial
products in the environment. Agents from sunlight to
chemicals, ionizing radiation, and oxygen radicals can
either directly damage bases or break the
phosphodiester backbone on which the bases reside.

We can reduce but probably never eliminate exposure.
Thus, we must rely on the elegant mechanisms our cells
have developed to repair damage. Individuals who
inherit mutations in DNA-damage response genes can
exhibit many clinical problems, including cancer
predisposition, neurodegeneration, increased
cardiovascular disease, and premature aging.1 Thus, a
broad range of physiologic processes depends on
cellular responses to DNA damage.

But for all the important roles such responses play,
little effort has been directed at manipulating these
pathways for clinical benefit. Depending on the
setting, one could envision clinical benefit arising
from either inhibition or augmentation of these
pathways. I believe that much of the basic
understanding is already in place to begin seriously
thinking about how to modulate the activity of these
pathways to benefit patients. Such work could place
DNA-damage response modulation at the foundation for a
set of new therapies and preventive drugs.


Cellular DNA can be damaged in several ways: Bases can
be covalently altered, the phosphodiester backbone can
break on one or both strands, or chemical interstrand
cross-links can be introduced. Predictably, different
mechanisms are needed to repair these broadly
differing types of damage.

Nucleotide-excision repair, base-excision repair,
O6-alkly-transferase, and mismatch repair serve to
deal with base damage. Single-strand breaks are easily
fixed, but double-strand breaks require the complex
mechanisms of nonhomologous end-joining and homologous
recombination, the latter only being useful in late S,
G2 or M phases of the cell cycle, when homologous
chromosomes are present in the cell.

For optimal responses, DNA repair must coordinate with
other cellular processes, such as cell-cycle
progression and programmed cell death. All somatic
eukaryotic cells arrest progression through the cell
cycle when their DNA is damaged, presumably because
optimal repair of the damage would be a mechanistic
challenge if the cell continued to replicate DNA or
segregate chromosomes.2 Cell-cycle arrest occurs at
multiple stages: G1, S, and G2/M.

Multicellular organisms can also deal with DNA damage
through programmed cell death. The DNA- damage
response gene, p53, is an important mediator of this
cell-death pathway.3 Such cellular-suicide mechanisms
can eliminate cells that could present problems for
the whole organism because of alterations in the DNA
or difficulties in dealing with stressful stimuli. The
importance of these pathways in cancer prevention is
illustrated by the fact that individuals who inherit
mutations in any one of the many genes that
participate in these stress-induced signal
transduction pathways have a very high incidence of
cancer. The list of such genes includes BRCA1, BRCA2,
p53, ATM, CHK2, and many genes directly involved in
the repair of damaged DNA.


Although these cellular-suicide mechanisms may protect
the organism in some physiologic settings, such as by
preventing cancer, the double-edged sword is that
these same DNA-damage response pathways that help
prevent cancer can also contribute to debilitating
disease processes. For example, neuronal cell death
after stroke or in several neurodegenerative disorders
likely occurs via programmed cell death responding to
cellular stress signals. A recent link of the p53
tumor suppressor gene to Huntington disease and
potentially other neurodegenerative diseases supports
this notion.4 

A similar problem may occur in ischemia-reperfusion
injuries, such as those that occur in heart attack and
stroke. Modulation of p53-mediated cellular-suicide
activity may influence the amount of tissue injury.5
Conversely, p53 induction by oxidative damage may help
reduce the development of atherosclerosis, perhaps by
suppressing the growth or enhancing the death of cells
involved in causing atherosclerotic lesions.6,7 These
examples illustrate the spectrum of clinical settings
in which stress-response signaling pathways

>From the perspective of cancer, DNA damage causes the
disease, but it is also used to treat the disease via
radiation and many chemotherapeutic agents. Moreover,
DNA damage is responsible for many of the toxicities
incurred in treatment, including bone marrow
suppression, hair loss, and gastrointestinal
toxicites. Recent work has demonstrated that
DNA-damage pathways are activated very early in the
process of tumor development,8,9 and elegant
epidemiologic studies demonstrated long ago that
exposure to environmental agents contributes to the
development of the vast majority of human cancers.10
Thus, enhancing the damage-response pathways could be
a powerful approach to cancer prevention. Mice
carrying extra copies of genes such as p53 appear
relatively resistant to cancer,11 providing further
credibility for this approach.

DNA-damaging stress from various sources can initiate
signal-transduction pathways, typically beginning with
activation of initiating kinases, and then signaling
through transducing targets that ultimately affect
cellular fate. The ability of cells in multicellular
organisms to undergo programmed cell death or
cell-cycle arrest helps to reduce the frequency with
which cellular changes contribute to malignant

The other side of the cancer coin is that blocking
these damage response pathways could be used to
enhance the effectiveness of cancer therapies by
making tumor cells more sensitive to DNA-damaging
therapies such as radiation and cytotoxic
chemotherapies. Since many of the proteins involved in
these signaling pathways are kinases, they represent
good targets for generation of small-molecule
inhibitors. Though normal tissues might also be
sensitized by such inhibitors, it is possible to
circumvent this problem by delivering the radiation
directly to the tumor by physical or biological
targeting, such as with isotopes conjugated to
tumor-directed antibodies.

In addition, somatic mutations in tumors might make
them inherently more sensitive to these inhibitions
than normal cells. Such a paradigm was recently
suggested with the increased sensitivity of
Brca2-mutant tumor cells to inhibition by PARP
inhibitors.12,13 The harsh microenvironment of tumor
cells, including hypoxia, nutrient deprivation, and
acid pH might even make tumor cells in vivo
selectively susceptible to inhibition of cellular
stress-response pathways without having to add
chemotherapy or radiation therapy. Finally, blocking
stress-induced apoptotic pathways may help protect
normal tissues from the toxicities of chemotherapy and
radiation therapy. Such interventions could
potentially reduce bone marrow suppression and damage
to gastrointestinal mucosa.

As mentioned above, DNA-damage response pathways
probably also contribute to the pathogenesis of
neurodegenerative and cardiovascular diseases. Thus,
modulation of these pathways also has the potential to
intervene in these common clinical settings. Blockade
of p53 or other apoptotic signals could ameliorate
some of the cell death that leads to heart damage
following heart attack, neuronal damage following
stroke, or neurodegeneration seen in certain inherited
disorders. Conversely, stimulation of the p53 pathway
may reduce development of atherosclerosis and perhaps
other disorders linked to oxidative stress.6,7 

Modulation of DNA-damage signaling pathways has the
potential to change the course of some of the most
common and debilitating diseases affecting humankind.
We would be remiss not to pursue the rich
opportunities in this area and actively develop drugs
or biologics that affect these pathways. If we can
manipulate the molecular events that determine
cellular outcome following stressful exposures, we may
have the opportunity to influence cancer,
cardiovascular disease, and neurologic disorders. I
haven't even mentioned another disorder linked to
chronic oxidative stress, and familiar to many of us
who have watched the body of DNA-damage research grow
– namely, aging.

. . .


. . .

On Oct. 5, 1947, in the first televised White House address, President Truman asked Americans to refrain from eating meat on Tuesdays and poultry on Thursdays to help stockpile grain for starving people in Europe. 

-- John
John Jacobus, MS
Certified Health Physicist
e-mail:  crispy_bird at yahoo.com

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