DNA Damage

It is evident from several studies that the genetic damage occurs in multiple steps that include small-scale insertions, deletions of DNA bases/segments, DNA base changes/modifications, microsatellite instability, chromosomal changes/loss, and translocation of segments.1516 A number of physical and chemical agents can trigger genomic damage by directly attacking DNA. Among these agents, reactive oxygen species (ROS) are the most documented. ROS-induced DNA damage is the most common mechanism for toxic occupational and environmental agents, such as asbestos, silica, ozone, and ultraviolet and ionizing radiations. During normal physiological or subtle pathophysiological processes, moderate overproduction of ROS is antagonized by the efficient endogenous antioxidant system. In contrast, enhanced ROS generation will overwhelm antioxidant defense, resulting in the interaction of ROS with a number of intracellular targets, especially DNA, lipids, and proteins.

Sustained, enhanced production of ROS can cause cumulative DNA damage, including base modifications, strand breaks, and large segment deletions. It can also convert cellular constituents into second-generation reactive intermediates capable of inducing further damage.17 ROS damages DNA by attacking the nucleic acid bases, deoxyribose residues, or the phosphodiester backbone. The most important base attack of ROS is hydroxyl radical fOH)-mediated purine oxidation.18 •OH reacts with purines to form 8-oxo-7,8-dihydrodeoxyguanosine (8-oxo-dG) or 8-oxo-7,8 dihydrodeoxyadenosine (8-oxo-dA), which alters the base-pairing properties of guanines or adenine. •OH can also react with pyrimidines to generate pyramidine glycols by adding the 5,6 double bond of pyrimidines. In addition, by an indirect mechanism, •OH can induce DNA single-strand breaks through hydrogen abstraction from the 5-methyl group of thymine or the DNA sugar moieties.19 The progressive accumulation of such oxidatively damaged DNA will obviously increase the incidence of cancer.

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