Oxidative DNA Damage and Repair: Mechanisms, Mutations, and Relation to Diseases

Dear Colleagues,

For higher eukaryotic aerobic organisms, the paradox of life in an aerobic environment, or the 'Oxygen Paradox', reflects the fact that these organisms rely on oxygen in their life cycle, yet oxygen is inherently damaging for them. This damage by overproduced reactive oxygen species or reactive nitrogen species (ROS or RNS) during the condition known as oxidative stress is payback for the ability to obtain about 18 times more energy from food sources via oxygen-dependent complete oxidation in mitochondria than is possible via glycolysis.

Oxidative DNA damage (ODD) is an unavoidable consequence of oxidant-dependent cellular metabolism, with an increase in damage during oxidative stress by toxic insults such as ionizing radiation, UV light, tobacco smoking, pollutants, and infections. ODD can occur as single- or double-strand breaks, nucleobase modification, base transversions, free base release, and DNA–DNA and DNA–protein crosslinks. Although a large variety of products of ODD have been reported, only a fraction of these have received appreciable attention, most notably 8-oxo-7,8-dihydroguanine (8-oxoGua), a ubiquitous guanine oxidation product. This DNA lesion has received intense research interest and has been widely used as a biomarker of oxidative stress, ODD, and mutagenesis in research and clinical studies. Methods of the analysis of oxidative DNA lesions include high-performance liquid chromatography (HPLC), mass spectrometric (MS) techniques such as gas chromatography–mass spectrometry (GC–MS), 32P-post-labeling assays, immunoassays, and comet assay.

An important consequence of extensive ODD is the malfunction of physiological mechanisms maintaining the cell cycle and metabolic homeostasis, which can lead to tissue injury and carcinogenesis. Unrepaired ODD and repair intermediates are directly linked to spontaneous mutagenesis. In addition, ODD can affect gene expression by interfering with transcription factor binding. The repair of oxidatively modified DNA is essential to maintain genomic stability. To cope with the oxidatively induced damage in DNA, a large variety of DNA damage-specific removal and repair enzymes have evolved in mammalian cells. The DNA damage response is a stepwise hierarchical process based on a relay system from sensors to transducers to effectors that enables a single DNA oxidative lesion to modulate a multitude of pathways. Functions and effects of many DNA repair machinery components remain poorly understood. It is generally believed that oxidatively generated DNA lesions in mammalian cells are repaired by overlapping the nucleotide excision repair (NER) pathway, which removes DNA helix-distorting bulky DNA lesions, and base excision repair (BER), which repairs small non-bulky lesions.

There is fast accumulating evidence that ODD is an important factor in the development of a large variety of pathological conditions, including cancer, cardiovascular diseases such as myocardial infarction and stroke, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, autoimmune diseases such as rheumatoid arthritis and systemic lupus, depression, AIDS, and premature and normal aging. Elevated levels of oxidatively damaged DNA, such as 8-oxoGua, have been measured in a number of pathological conditions, and it has been hypothesized that such damages play a critical role in these conditions. However, there is still no clear understanding of whether the elevated levels of ODD in pathological tissues indicate that it was this damage that led to the pathology, or if it was a mere consequence of abnormal physiological functioning of such tissues. 

We cordially invite you to contribute your original research as well as review articles to this Special Issue aimed at critically examining the biological significance of ODD, mechanisms of ODD and its repair, methods of analysis of ODD, its role in mutagenesis and in the development and manifestation of pathological conditions at the molecular, cellular, biochemical, and physiological levels, as well as clinical and pre-clinical research in the field of ODD and the role of oxidative stress in ODD.

Prof. Dr. Marina Roginskaya
Prof. Dr. Yuriy Razskazovskiy
Prof. Dr. Alexandros Georgakilas
Guest Editors

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• oxidative DNA damage
• oxidative stress
• reactive oxygen species
• biomarkers
• bioassays
• 8-oxo-7,8-dihydroguanine
• mutagenesis
• DNA repair enzymes
• base excision repair
• nucleotide excision repair
• neurodegenerative diseases
• cardiovascular diseases
• cancer