The Mechanics of Mutation

During the course of evolution, a complex set of enzymatic mechanisms developed to maintain the fidelity of DNA before and during its replication. Any damage to this apparatus, including the structure of DNA itself, may result in mutation. 

Recently, a quite different model has been proposed that accounts for the appearance of many kinds of mutations, including base pair substitutions, additions and deletions, and small chromosomal mutations of the type that would usually be classified as gene mutations. The model accounts for frequent palindromic sequences (more exactly, imperfect palindromes or quasipalindromes) in DNA that can predispose to alternative DNA structures (e.g., clover leaves) that differ from the usual double helix. The alternative or secondary structures can then be acted on by any of a variety of DNA-processing enzymes in ways that may ultimately lead to mutations. The details of these processes are only now becoming manifest, but the general model clearly explains many hitherto mysterious mutational phenomena.371 

The change may occur spontaneously (by internal proton migration, for instance) or as the result of reaction with 

An elegant and extremely sophisticated set of mutation-avoidance mechanisms operates within cells so effective are these that only once in 103-108 possibilities is a potentially mutagenic lesion not circumvented. These mechanisms operate at three distinct times during the cell cycle before, during, and shortly after ENA replication. 

The first mechanism operates to remove ENA damage, whereupon the missing genetic information is resynthesized chemically according to instructions received from the complementary strand (e.g., excision repair or direct reversal of damage, as by photoreactivation and dealkylation). The second mechanism acts as a part of, or in close association with, 

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Mutagen specificity meant something different to plant breeders than it did to geneticists working on the mechanisms of mutation. For plant breeders, the central problem was phenotypic specificity, where the outcome was a phenotypic characteristic such as disease resistance or straw stiffness (in the case of barley). Here, the ends outweighed the means in economic importance. More fundamental locus specificity and the origins of mutational outcomes were less important to breeders (Auerbach 1976 453-454). 

Let us continue to discuss the mechanisms of mutations that commonly afflict the gene for p53. Within a few paragraphs we will leam some of the most likely mechanisms that account for lower rates of cancer with diets high in fruits and vegetables-... 

This apparent paradox is resolved by the mechanisms of mutation and recombination that provide for a small but essential amount of genetic change to occur in each... 

Many of the results in the first three of these categories have been obtained from experiments conducted with isolated (purified) DNA. These do not in all cases represent the situation in the living cell, and in particular the mechanism of mutation induction as a consequence of these reactions occur-... 

If he is convinced that the matter is important enough to merit serious personal involvement on his part, with the directly relevant work of assessing the impact of mutations on man and looking for possible changes in the mutation rate, he will be led far from the basic research on the mechanisms of mutation in which he was first interested. If, however, he leaves the task to others, there is a reasonable likelihood that it may not get tackled at all. Social concern in such matters has a tendency to arise first among basic scientists as an outcome of their own research, and it is often not shared in full measure by their more applied colleagues. 

Genetic Control. Manipulation of the mechanisms of inheritance of the insect pest populations has occurred most successhiUy through the mass release of steri1i2ed males, but a variety of other techniques have been studied, including the environmental use of chemostetilants and the mass introduction of deleterious mutations, eg, conditional lethals and chromosomal translocations (58 ndash 60) (see Genetic engineering). 

Another important protein of the Clp family is ClpB which possesses ATPase activity. In a clpB mutation, 45% of the denatured and aggregated protein arising transiently after the transfer of an E. coli culture from 30 to 45 °C is stabilized [14]. ClpB seems to play an important role in the renaturation or proteolysis of the aggregated proteins, but the mechanism of action of ClpB is not yet known. One can suppose that it might participate in the resolubilization of aggregated proteins. 

The mechanism of acquired resistance in Pseudomonas aeruginosa is different. Chromosomal mutations result in the increase of a specific outer membrane protein with a concomitant reduction in divalent cations. Polymyxins bind to the outer membrane at sites normally occupied by divalent cations, and therefore it is thought that a reduction in these sites will lead to decreased binding of the antibiotic with a consequent decreased susceptibility of the cell. 

One of the greatest problems in treatment with MTX and other anti-folates is the fact that the cancer cells develop immunity to the drugs. It has been found34 that this immunity is due mainly to DHFR mutations where some amino-acid residues are replaced by others which do not bind to anti-folates. The desire to better understand the mechanism of binding of anti-folates to DHFR, in order that this problem will be remediated, has led to numerous experimental studies. In addition, theoretical studies have complemented the attempts to elucidate the mechanism. 

All three of these predictions from this minimal model are manifest in the etiology of prion disease an inversely proportional relationship between PrPc expression and prion incubation period in transgenic mice predisposition by relatively subtle mutations in the protein sequence and a requirement for molecular homogeneity between PrPSc and PrPc for efficient prion propagation [4, 5, 20]. It is clear that a full understanding of prion propagation will require knowledge both of the structure of PrPc and PrPSc and of the mechanism of conversion between them. 

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