DNA Repair:- Mutations Are Linked to Cancer
The best way to illustrate the importance of DNA repair is to consider the effects of unrepaired DNA damage (a lesion). The most serious outcome is a change in the base sequence of the DNA, which, if replicated and transmitted to future cell generations, becomes permanent. A permanent change in the nucleotide sequence of DNA is called a mutation. Mutations can involve the replacement of one base pair with another (substitution mutation) or the addition or deletion of one or more base pairs (insertion or deletion mutations). If the mutation affects nonessential DNA or if it has a negligible effect on the function of a gene, it is known as a silent mutation. Rarely, a mutation confers some biological advantage. Most nonsilent mutations, however, are deleterious.
In mammals there is a strong correlation between the accumulation of mutations and cancer. A simple test developed by Bruce Ames measures the potential of a given chemical compound to promote certain easily detected mutations in a specialized bacterial strain (Fig. 1). Few of the chemicals that we encounter in daily life score as mutagens in this test. However, of the com pounds known to be carcinogenic from extensive animal trials, more than 90% are also found to be mutagenic in the Ames test. Because of this strong correlation between mutagenesis and carcinogenesis, the Ames test for bacterial mutagens is widely used as a rapid and in expensive screen for potential human carcinogens.
FIGURE 1 Ames test for carcinogens, based on their mutagenicity. A strain of Salmonella typhimurium having a mutation that inactivates an enzyme of the histidine biosynthetic pathway is plated on a histidine-free medium. Few cells grow. (a) The few small colonies of S. typhimurium that do grow on a histidine-free medium carry spontaneous back-mutations that permit the histidine biosynthetic pathway to operate. Three identical nutrient plates (b), (c), and (d) have been inoculated with an equal number of cells. Each plate then receives a disk of filter paper containing progressively lower concentrations of a mutagen. The mutagen greatly increases the rate of back-mutation and hence the number of colonies. The clear areas around the filter paper indicate where the concentration of mutagen is so high that it is lethal to the cells. As the mutagen diffuses away from the filter paper, it is diluted to sublethal concentrations that promote back-mutation. Mutagens can be compared on the basis of their effect on mutation rate. Because many compounds undergo a variety of chemical transformations after entering a cell, compounds are sometimes tested for mutagenicity after first incubating them with a liver extract. Some sub stances have been found to be mutagenic only after this treatment.
The genome of a typical mammalian cell accumulates many thousands of lesions during a 24-hour period. However, as a result of DNA repair, fewer than 1 in 1,000 becomes a mutation. DNA is a relatively stable molecule, but in the absence of repair systems, the cumulative effect of many infrequent but damaging reactions would make life impossible.
