Mutation Research/Reviews in Mutation Research
ReviewRole of oxidatively induced DNA lesions in human pathogenesis
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.
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