Effect of Oxidative Stress on DNA Repairing Genes

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Oxidative DNA damage has been thought to contribute to the general decline in cellular functions that are associated with a variety of diseases including Alzheimer disease, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, atherosclerosis, ischemia/reperfusion neuronal injuries, degenerative disease of the human temporomandibular-joint, cataract formation, macular degeneration, degenerative retinal damage, rheumatoid arthritis , multiple sclerosis , muscular dystrophy, diabetes mellitus, human cancers as well as the aging process itself. Oxidative stress occurs when the production of the reactive oxygen species (ROS) exceeds natural antioxidant defence mechanisms. There are several sources that form the ROS. Most of ROS come from the endogenous sources as by-products of normal and essential metabolic reactions, such as energy generation from mitochondria or the detoxification reactions involving the liver cytochrome P-450 enzyme system. There are also exogenous ROS sources including exposure to cigarette smoke, environmental pollutants such as emission from automobiles and industries, consumption of alcohol in excess, asbestos, exposure to ionizing radiation, and bacterial, fungal or viral infections. ROS cause damage to biomolecules such as lipid, proteins and DNA by attaching. ROS may directly attack DNA, either the sugar, phosphate or purine and pyrimidine bases. On the other hand, oxidative damage may be indirect by rising of intracellular Ca+2 ions. Free radical-mediated reactions can cause structural alterations in DNA (e.g., nicking, base-pair mutations, rearrangement, deletions insertions and sequence amplification). Degradation of the bases will produce numerous products, including 8-OH-Gua, hydroxymethylurea, urea, thymine glycol; thymine and adenine ring opened and saturated products. Most oxidized bases in DNA are repaired by base excision repair (BER). BER consists of four main steps. The first step involves the removal of the oxidised base by a specific DNA glycosylase, yielding an apurinic/apyrimidinic (AP) site. In the second step, an AP endonuclease removes the deoxyribose phosphate group from the AP site generating a single nucleotide gap. A DNA polymerase, thought to be predominantly DNA polymerase b, fills this gap. Finally, a DNA ligase, probably DNA ligase III, seals the stand break and completes the repair process. This chapter mainly deals with: (i) formation of ROS in physiological and pathological conditions, (ii ) ROS-mediated DNA damage, leading to cellular pathology and ultimately to cell death (iii) Oxidative DNA damage repair systems, (iv) The molecular mechanism of ROS-mediated diseases such as cancer, cardiovascular disease, neurodegenerative diseases, inflammatory disease, ischemia-reperfusion injury and aging.