Dna damage and cáncer

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review article
MOLECULAR ORIGINS OF CANCER

DNA Damage, Aging, and Cancer
Jan H.J. Hoeijmakers, Ph.D. NA damage has emerged as a major culprit in cancer and many diseases related to aging. The stability of the genome is supported by an intricate machinery of repair, damage tolerance, and checkpoint pathways that counteracts DNAdamage. In addition, DNA damage and other stresses can trigger a highly conserved, anticancer, antiaging survival response that suppresses metabolism and growth and boosts defenses that maintain the integrity of the cell. Induction of the survival response may allow interventions that improve health and extend the life span. Recently, the first candidate for such interventions, rapamycin (alsoknown as sirolimus), has been identified.1 Compromised repair systems in tumors also offer opportunities for intervention, making it possible to attack malignant cells in which maintenance of the genome has been weakened. Time-dependent accumulation of damage in cells and organs is associated with gradual functional decline and aging.2 The molecular basis of this phenomenon is unclear,3-5 whereas incancer, DNA alterations are the major culprit. In this review, I present evidence that cancer and diseases of aging are two sides of the DNAdamage problem. An examination of the importance of DNA damage and the systems of genome maintenance in relation to aging is followed by an account of the derailment of genome guardian mechanisms in cancer and of how this cancerspecific phenomenon can beexploited for treatment.

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From the Department of Genetics, Cancer Genomics Center, Erasmus University Medical Center, Rotterdam, the Netherlands. Address reprint requests to Dr. Hoeijmakers at the Department of Genetics, Cancer Genomics Center, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands, or at j.hoeijmakers@erasmusmc.nl. This article(10.1056/NEJMra0804615) was updated on November 4, 2009, at NEJM. org. N Engl J Med 2009;361:1475-85.
Copyright © 2009 Massachusetts Medical Society.

DNA Da m age a nd Aging
Biologic molecules are susceptible to spontaneous chemical reactions, mostly hydrolysis. Enzymatic reactions have an error rate, and their reaction products (including free radicals, such as reactive oxygen and nitrogen species)2,6 can haveharmful effects on other biologic molecules. Furthermore, elements in the environment — x-rays, ultraviolet (UV) radiation, and numerous chemicals — continuously damage cellular structures.3-5 DNA is an important target for time-dependent deterioration, as highlighted by the rapidly expanding family of rare inherited disorders called segmental progeroid syndromes, in which genome maintenance iscompromised and many features of aging are accelerated7,8 (for details see the Supplementary Appendix, available with the full text of this article at NEJM.org). These syndromes indicate that DNA is a critical target of aging and that genome maintenance is a major antiaging mechanism.

The M agni t ude of DNA Da m age
DNA is the only biologic molecule that relies solely on repair of existingmolecules, without any remanufacture; accumulates damage over a lifetime; and is represented by only one copy in most cells (with maternal and paternal DNA considered to be

n engl j med 361;15

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The New England Journal of Medicine Downloaded from nejm.org by Gabriela Cevallos on May 10, 2011. For personal use only. No other uses without permission. Copyright© 2009 Massachusetts Medical Society. All rights reserved.

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Figure 1. Sources and Consequences of DNA Damage. DNA damage can be induced by exogenous physical agents, by endogenous chemical genotoxic agents that are the products of metabolism, such as reactive oxygen species (ROS), or by spontaneous chemical reactions, such as...