Review
Role of oxidatively induced DNA lesions in human pathogenesis

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Abstract

Genome stability is essential for maintaining cellular and organismal homeostasis, but it is subject to many threats. One ubiquitous threat is from a class of compounds known as reactive oxygen species (ROS), which can indiscriminately react with many cellular biomolecules including proteins, lipids, and DNA to produce a variety of oxidative lesions. These DNA oxidation products are a direct risk to genome stability, and of particular importance are oxidative clustered DNA lesions (OCDLs), defined as two or more oxidative lesions present within 10 bp of each other. ROS can be produced by exposure of cells to exogenous environmental agents including ionizing radiation, light, chemicals, and metals. In addition, they are produced by cellular metabolism including mitochondrial ATP generation. However, ROS also serve a variety of critical cellular functions and optimal ROS levels are maintained by multiple cellular antioxidant defenses. Oxidative DNA lesions can be efficiently repaired by base excision repair or nucleotide excision repair. If ROS levels increase beyond the capacity of its antioxidant defenses, the cell's DNA repair capacity can become overwhelmed, leading to the accumulation of oxidative DNA damage products including OCDLs, which are more difficult to repair than individual isolated DNA damage products. Here we focus on the induction and repair of OCDLs and other oxidatively induced DNA lesions. If unrepaired, these lesions can lead to the formation of mutations, DNA DSBs, and chromosome abnormalities. We discuss the roles of these lesions in human pathologies including aging and cancer, and in bystander effects.

Section snippets

Induction and processing of oxidative DNA lesions in human cells and tissues

Elevated ROS levels can create oxidative stress in a cell and chronic exposure to this stress can result in permanent changes in the genome [1], [2]. It is generally accepted that the accumulation of oxidative DNA lesions may promote mutagenesis, human pathogenesis and loss of homeostasis. These oxidative lesions can be induced not only by ROS generated by exposure to exogenous agents including ionizing or non-ionizing radiation (IR), drugs, and other chemicals such as metals [3], [4], [5], [6]

Oxidative DNA damage and aging

There is considerable evidence suggesting that oxidative stress plays a critical role in both in vitro senescence and in vivo aging [52], [53]. Cells of laboratory mice were reported to reach senescence after 4–5 population doublings under standard cell culture conditions, however, the onset of senescence was substantially delayed when the O2 level was reduced from 21% to 3% [54]. The discovery that lower O2 increased plating efficiencies [55] was an important milestone in development of the

Oxidative DNA damage and cancer

That oxidative stress-induced DNA lesions may contribute to carcinogenesis is suggested by the increased cancer susceptibility of persons with a variety of chronic inflammatory diseases, such as ulcerative colitis, viral hepatitis, prostatitis, Helicobacter pylori infection, parasitic diseases, and others [3]. In these diseases, cancer induction may be a pathological consequence of elevated ROS levels which lead to increased steady-state levels of oxidative DNA damage which in turn leads to a

Oxidative DNA damage is induced in bystander cell populations

Intercellular communication has been well studied in relation to bystander effects in vitro and in vivo. Bystander effects are seen in cell populations neighboring or sharing media with damaged or stressed cells [98] including those under biological stresses such as aging and cancer [99]. Some examples of bystander effects include increased mutations, DNA DSB formation, and apoptosis [98], [100], [101].

The signaling in vitro has been shown to be reminiscent of the inflammatory response mediated

Conclusions

There is an abundance of evidence implicating ROS as one source of DNA damage associated with aging, cancer, stress signaling, and other conditions. However, ROS are essential to numerous cellular processes including apoptosis [122], cell growth [123] and the activation of redox system proteins [97]. In addition, ROS play a role in acquired immunity, killing bacteria and other pathogens, when produced by macrophages and neutrophils [124]. Moreover, extreme hypoxia (less than 1% O2) also

Conflict of interest statement

The authors declare that there is no conflict of interest.

Acknowledgements

This work has been partially supported by funds provided to A.G. by the Biology Department of East Carolina University and a Research/Creative Activity Grant to A.G. This work was also supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health.

References (129)

  • S. Nowsheen et al.

    Accumulation of oxidatively induced clustered DNA lesions in human tumor tissues

    Mutat. Res.

    (2009)
  • L. Harrison et al.

    In vitro repair of synthetic ionizing radiation-induced multiply damaged DNA sites

    J. Mol. Biol.

    (1999)
  • S.M. Cunniffe et al.

    An AP site can protect against the mutagenic potential of 8-oxoG when present within a tandem clustered site in E. coli

    DNA Repair (Amst.)

    (2007)
  • A.M. Wilstermann et al.

    Base excision repair intermediates as topoisomerase II poisons

    J. Biol. Chem.

    (2001)
  • Y. Pommier et al.

    Repair of topoisomerase I-mediated DNA damage

    Prog. Nucleic Acid Res. Mol. Biol.

    (2006)
  • N. Yang et al.

    Attempted base excision repair of ionizing radiation damage in human lymphoblastoid cells produces lethal and mutagenic double strand breaks

    DNA Repair (Amst.)

    (2004)
  • A Memisoglu et al.

    Base excision repair in yeast and mammals

    Mutat. Res.

    (2000)
  • G. Slupphaug et al.

    The interacting pathways for prevention and repair of oxidative DNA damage

    Mutat. Res.

    (2003)
  • D.R. Marenstein et al.

    Substrate specificity of human endonuclease III (hNTH1). Effect of human APE1 on hNTH1 activity

    J. Biol. Chem.

    (2003)
  • R. Franco et al.

    Oxidative stress, DNA methylation and carcinogenesis

    Cancer Lett.

    (2008)
  • F.L. Muller et al.

    Trends in oxidative aging theories

    Free Radic. Biol. Med.

    (2007)
  • D. Wion et al.

    PO(2) matters in stem cell culture

    Cell Stem Cell

    (2009)
  • C.J. Bakkenist et al.

    Initiating cellular stress responses

    Cell

    (2004)
  • U. Herbig et al.

    Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a)

    Mol. Cell

    (2004)
  • A. Nakamura et al.

    Techniques for gamma-H2AX detection

    Methods Enzymol.

    (2006)
  • W. Klapper et al.

    Telomere biology in human aging and aging syndromes

    Mech. Ageing Dev.

    (2001)
  • T. von Zglinicki

    Oxidative stress shortens telomeres

    Trends Biochem. Sci.

    (2002)
  • T. von Zglinicki et al.

    Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence?

    Exp. Cell Res.

    (1995)
  • C.W. Greider et al.

    Identification of a specific telomere terminal transferase activity in Tetrahymena extracts

    Cell

    (1985)
  • K. Furumoto et al.

    Age-dependent telomere shortening is slowed down by enrichment of intracellular vitamin C via suppression of oxidative stress

    Life Sci.

    (1998)
  • N.M. Druzhyna et al.

    Mitochondrial DNA repair in aging and disease

    Mech. Ageing Dev.

    (2008)
  • D.L. Ellsworth et al.

    Genomic instability in histologically normal breast tissues: implications for carcinogenesis

    Lancet Oncol.

    (2004)
  • T Yu et al.

    Endogenous expression of phosphorylated histone H2AX in tumors in relation to DNA double-strand breaks and genomic instability

    DNA Repair (Amst.)

    (2006)
  • J. Lindsey et al.

    In vivo loss of telomeric repeats with age in humans

    Mutat. Res.

    (1991)
  • M.S Cooke et al.

    Oxidative DNA damage: mechanisms, mutation, and disease

    FASEB J.

    (2003)
  • S.P. Hussain et al.

    Radical causes of cancer

    Nat. Rev. Cancer

    (2003)
  • P. O’Neill et al.

    Radiation chemistry comes before radiation biology

    Int. J. Radiat. Biol.

    (2009)
  • T.J. McMillan et al.

    Cellular effects of long wavelength UV light (UVA) in mammalian cells

    J. Pharm. Pharmacol.

    (2008)
  • J.E. Klaunig et al.

    The role of oxidative stress in carcinogenesis

    Annu. Rev. Pharmacol. Toxicol.

    (2004)
  • M. Ott et al.

    Mitochondria, oxidative stress and cell death

    Apoptosis

    (2007)
  • F Galli et al.

    Oxidative stress and reactive oxygen species

    Contrib. Nephrol.

    (2005)
  • C. Kohchi et al.

    ROS and innate immunity

    Anticancer Res.

    (2009)
  • J.F. Ward

    The complexity of DNA damage: relevance to biological consequences

    Int. J. Radiat. Biol.

    (1994)
  • B.M. Sutherland et al.

    Clustered DNA damages induced in isolated DNA and in human cells by low doses of ionizing radiation

    Proc. Natl. Acad. Sci. U.S.A.

    (2000)
  • J. Nakamura et al.

    Endogenous apurinic/apyrimidinic sites in genomic DNA of mammalian tissues

    Cancer Res.

    (1999)
  • H. Atamna et al.

    A method for detecting abasic sites in living cells: age-dependent changes in base excision repair

    Proc. Natl. Acad. Sci. U.S.A.

    (2000)
  • R. De Bont et al.

    Endogenous DNA damage in humans: a review of quantitative data

    Mutagenesis

    (2004)
  • C.M. Gedik et al.

    Establishing the background level of base oxidation in human lymphocyte DNA: results of an interlaboratory validation study

    FASEB J.

    (2005)
  • J.F. Ward

    Some biochemical consequences of the spatial distribution of ionizing radiation-produced free radicals

    Radiat. Res.

    (1981)
  • M.H. David-Cordonnier et al.

    Efficiency of incision of an AP site within clustered DNA damage by the major human AP endonuclease

    Biochemistry

    (2002)
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