Review
Oxidative DNA damage and disease: induction, repair and significance

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Abstract

The generation of reactive oxygen species may be both beneficial to cells, performing a function in inter- and intracellular signalling, and detrimental, modifying cellular biomolecules, accumulation of which has been associated with numerous diseases. Of the molecules subject to oxidative modification, DNA has received the greatest attention, with biomarkers of exposure and effect closest to validation. Despite nearly a quarter of a century of study, and a large number of base- and sugar-derived DNA lesions having been identified, the majority of studies have focussed upon the guanine modification, 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-OH-dG). For the most part, the biological significance of other lesions has not, as yet, been investigated. In contrast, the description and characterisation of enzyme systems responsible for repairing oxidative DNA base damage is growing rapidly, being the subject of intense study. However, there remain notable gaps in our knowledge of which repair proteins remove which lesions, plus, as more lesions identified, new processes/substrates need to be determined. There are many reports describing elevated levels of oxidatively modified DNA lesions, in various biological matrices, in a plethora of diseases; however, for the majority of these the association could merely be coincidental, and more detailed studies are required. Nevertheless, even based simply upon reports of studies investigating the potential role of 8-OH-dG in disease, the weight of evidence strongly suggests a link between such damage and the pathogenesis of disease. However, exact roles remain to be elucidated.

Introduction

The living cell is constantly exposed to potentially damaging free radical species, whose origin may be intracellular, such as those arising from normal cellular metabolism, or extracellular, produced as a consequence, for example, of exposure to ultraviolet radiation, or ionising radiations. Of particular interest are the reactive oxygen species (ROS), which include the highly reactive hydroxyl radical (radical dotOH), superoxide radical (O2radical dot), and non-radical hydrogen peroxide (H2O2). Cellular targets for oxidative modification by ROS include DNA, lipids, and proteins, and the order of preference for modification depends upon a number of factors, such as location of ROS production, relative ability for the biomolecule to be oxidised, and availability of metal ions. To combat attack from ROS, and other free radicals, living cells have acquired a number of defences. At its simplest, this defence takes the form of low molecular weight compounds, antioxidants such as vitamin C, and vitamin E, which intercept free radicals, becoming radicals themselves, albeit less reactive, preventing damage to cellular biomolecules. Other, more complex approaches involve enzymes, such as superoxide dismutase, catalase and glutathione peroxidase, which have evolved to limit the levels of ROS.

Even in a normally functioning cell, there is a propensity for ROS to evade these defences, resulting in background levels of damage, which, in the short term, does not appear to be unduly detrimental to the cell. However, should there arise an imbalance between the ROS-producing, pro-oxidant factors, and the antioxidant defences, in favour of the former, levels of cellular damage will, in the first instance at least, increase. Whilst modified lipids and proteins may be removed via normal turnover of the molecules, damage to DNA is required to be repaired. As will be explored in this review, numerous pathways have evolved to perform this function. DNA, unlike proteins and lipids, once modified, cannot be replaced, and as a result has become a focus of much research interest, and its involvement in the pathogenesis of many diseases has been the focus of much speculation. Within this review, and taking into account many studies into a variety of diseases, the experimental basis for this speculation will be evaluated. Firstly however, our current understanding of the mechanisms involved in the interaction between ROS and DNA, and the subsequent production of damage, will be described.

Section snippets

Mechanisms of oxidative damage to DNA

Free radicals, most notably radical dotOH, react with organic compounds by addition and abstraction. Hydroxyl radical adds to double bonds of heterocyclic DNA bases and abstracts an H atom from the methyl group of thymine and from each of the C–H bonds of 2′-deoxyribose (reviewed in [1]). Further reactions of thus-formed C- or N-centred radicals of DNA bases and C-centred radicals of the sugar moiety result in a variety of final products.

Maintenance of DNA integrity

As detailed in the previous section, a large array of purine and pyrimidine-derived base lesions are reported to be produced following oxidative damage to DNA. The removal of these lesions by cellular repair processes is crucial in terms of limiting mutagenesis, cytostasis and cytotoxicity, which are possible consequences of the failure to repair these lesions. It has been demonstrated experimentally that many of these lesions can be removed by repair systems with differing, but in many cases

7,8-Dihydro-8-oxoguanine (8-OH-Gua)

The previous section has described how 8-OH-Gua may be generated opposite C, when G is oxidised in situ in DNA. The generation of 8-OH-Gua by agents, which are, for the most part, mutagenic has led to the suggestion that 8-OH-Gua itself might be mutagenic. Kuchino et al. [272] reported the ability of 8-OH-Gua in a single-stranded DNA oligomer to induce mis-reading by E. coli DNA polymerase I, not only of the lesion itself, but also of adjacent pyrimidines. Invariably, 8-OH-Gua formed in situ

Evidence of a role for oxidative DNA damage in disease

It is perhaps rather artificial to consider the role of oxidative DNA damage in disease, divorced from the potential effects of ROS themselves, and the subsequent oxidative stress (with concomitant lipid and protein damage). Nevertheless, increasing numbers of oxidatively modified DNA lesions are proposed to be appropriate, intermediate biomarkers of a disease endpoint. For this reason alone, the association between oxidative DNA damage and disease should be determined.

From the above sections,

Conclusions

The mechanisms involved in the generation of oxidatively damaged DNA are well understood, derived largely from experiences of radiation chemistry and biology. Given that the reactions, which occur in vitro, for the main part, also occur in vivo, this has allowed damaging species in the latter system to be deduced from ‘fingerprints’ of oxidative modification. Many lesions have been identified, and additions continue to be made to these numbers.

The numerous repair pathways and significant

Acknowledgements

MSC and MDE gratefully acknowledge financial support from the Food Standards Agency, Leicester Dermatology Research Fund and Arthritis Research Campaign. Certain commercial equipment or materials are identified in this paper in order to specify adequately the experimental procedure. Such identification does not imply recommendation or endorsement by the National Institute of Standards and Technology, nor does it imply that the materials or equipment identified are necessarily the best available

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