Dna Damage And Repair

The spontaneous mutation rate is low and differs among species. Among DNA microbes, the average spontaneous mutation rate per base pair varies approximately 100,000-fold from 10"10 to 10"5. In the human body, containing approximately 1014 cells, the mutation rate has been estimated to be 2 X 10"7 per gene per cell division (5). The mutation rate at specific loci has been studied in vivo in humans. For example, one assay tests the frequency of T cells that can grow in the presence of 6-thioguanine. These cells therefore have mutations altering the expression of the hypoxanthine phosphoribosyltransferase gene (HPRT). The frequency of HPRT mutations ranges from 3 X10"6 to 10 X10"6 (6). In kidney epithelial cells, the HPRT mutant frequencies are 20-fold higher than those found in T cells, possibly reflecting tissue-specific differences in mutation accumulation, differences in mutant frequency in vivo compared with cultured cells, or selection against HPRT deficiency in T cells.

The sources of DNA damage are protean. Environmental agents may act as mutagens, thus increasing the likelihood of the occurrence of mutations. Known agents in this category include ultraviolet (UV) light (the major source being exposure to sunlight), ionizing radiation, cigarette smoke, and various carcinogens such as asbestos and possible dietary factors. Whereas exposure to environmental factors frequently can be reduced or minimized by behavioral modification, other sources of DNA alteration are unavoidable: errors during DNA replication (which occur with each cell division), damage from by-products of normal cellular metabolism (including reactive oxygen species—superoxide anions, hydroxyol radicals, and hydrogen peroxide—derived from oxidative respiration), and products of lipid peroxidation. Other weak mutagens, such as thermally promoted hydrolysis of nucleotide residues by water, may occur under physiological conditions. Deamination results in base substitutions, such as the substitution of hypoxanthine for adenine or thymine for 5-methylcytosine. Therefore, even in nondividing cell populations, DNA damage occurs. Organisms have evolved a variety of mechanisms to compensate for these otherwise high mutation rates. These repair pathways have been studied in detail in a variety of model systems, which space does not allow us to discuss here. A very brief overview of the major repair pathways is presented here as a basis for understanding the relevant diseases in subsequent chapters. A recent comprehensive list of 130 human DNA repair-

related genes in humans has been reported based on searches of the draft sequence of the human genome (7). The reader is also referred to an outstanding summary and thorough discussion of the topic of DNA repair and mutagenesis by Friedberg and colleagues (8).

Dieting Dilemma and Skinny Solutions

Dieting Dilemma and Skinny Solutions

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