Oxidative Damage to DNA and Its Repair

Abstract

Free radicals, highly reactive chemical species, are produced in cells by ionizing radiation, a variety of chemicals, and by normal metabolic processes. About 60% of the DNA damage produced by ionizing radiation occurs from the radiolysis of water (Ward 1988). Here, the principal damaging species is the highly reactive hydroxyl radical (for reviews, see Hutchinson 1985; Teoule 1987; von Sonntag 1987; Kuwabara 1991; Breen and Murphy 1995). Other toxic agents such as paraquat, plumagen, and menadione are redox cyclers that generate intracellular superoxide anion (Kappus and Sies 1981). However, the most important contributor to the generation of free-radical-induced cellular damage is oxidative metabolism (Ames 1989; Ames et al. 1993; see Hauptmann and Cadenas, this volume). The principal noxious product of aerobic metabolism is the superoxide anion (for a review, see Cadenas 1989), which is converted to hydrogen peroxide by the action of cellular enzymes called superoxide dismutases. Hydrogen peroxide, in turn, is destroyed by catalases and peroxidases. It is the reaction of hydrogen peroxide with transition metals such as Fe⁺⁺ in a Fenton-type reaction that produces the damaging hydroxyl radical species (for reviews, see Imlay and Linn 1988; Aruoma et al. 1989a,b; Halliwell and Aruoma 1991; Breen and Murphy 1995). If a hydroxyl radical is formed in the vicinity of DNA, potentially mutagenic or lethal lesions can be produced. These lesions are identical to those produced in DNA by ionizing radiation and, accordingly, much of our knowledge about the formation, quantity, and structure of free-radical-induced DNA lesions has come from...