Dna Damage and Repair

Living organisms are constantly exposed to stress from environmental agents and from endogenous metabolic processes. An important factor is exposure to oxidative reagents or oxidative stress. The resulting reactive oxygen species (ROS) attack proteins, lipids and DNA. Since proteins and lipids are readily degraded and resynthesized, the most significant consequence of oxidative stress is thought to be DNA modifications, which can become permanent via the formation of mutations and other types of genomic instability.

Many different DNA base changes have been observed following oxidative stress, and these lesions are widely considered to instigate the development of cancer, aging, and neurological degradation. The attack on DNA by ROS generates a low steady-state level of DNA adducts that have been detected in the DNA from human cells. More than one hundred oxidative base modifications in DNA have been detected in human cells (Dizdaroglu), and a few of these are shown in Figure 1. The best-known and most widely studied oxidative DNA base adduct is 8-hydroxyguanosine (8-oxoG).

Oxidative DNA damage is thought to contribute to carcinogenesis, and studies have shown that it accumulates in cancerous tissue. Furthermore, the cumulative risk of cancer increases dramatically with age in humans (Ames), and cancer can in general terms be regarded as a degenerative disease of old age. There is evidence for the accumulation of oxidative DNA damage with age, based on studies mainly measuring the increase in 8-oxoG, the best-known and most widely studied oxidative DNA base lesion.

Figure 1 Examples of DNA base modifications observed in human tissue. SOURCE: Modified from: Dizdaroglu, M. "Chemical Determination of Free Radical-Induced Damage to DNA." Free Radical Biology and Medicine 10 (1991): 225-242.

DNA base damage also can occur after direct attack by external sources. Irradiation from various sources can directly damage bases in DNA. For example, ultraviolet irradiation from exposure to sunlight creates certain DNA lesions. Irradiation from γ-ray sources, such as X-rays, leads to many different kinds of lesions in DNA, including base modifications, sites with a loss of base, and breaks in the DNA strand. Since DNA contains two strands running in parallel but opposite directions, breaks can be either single-stranded or double-stranded. A large number of components of food intake can directly damage DNA. These include carcinogens and chemicals that cause DNA damage, either by direct reactions or via metabolic modification. For example, aromatic amines are found in variety of foods and are known to cause DNA damage and to be highly mutagenic. A number of poisons work by attacking the DNA and damaging it. An example of this is the poisonous gas nitrogen mustard, which causes modification of DNA bases and also can link DNA bases on opposite DNA strands. These cause serious havoc in the cell by completely blocking the progression of polymerases.