© Ana Amorim

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...


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.

<p>Michael Kastan</p>

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.67 These examples illustrate the spectrum of clinical settings in which stress-response signaling pathways participate.

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,89 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.


Michael Kastan

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 transformation.

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.1213 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.67

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.

Michael Kastan is director of the Cancer Center and chair of the Department of Hematology-Oncology at St. Jude Children's Research Hospital. He discovered the p53 tumor suppressor protein's role in cellular responses to DNA damage and has continued to elucidate steps involved in DNA-damage response pathways.

He can be contacted atmichael.kastan@stjude.org.

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