Mutation molecular mechanism

In approaching the study of the molecular mechanisms of heredity, this chapter first discusses the structural and functional roles of the genetic material, DNA. This includes an analysis of its replication and susceptibility to mutation. The health-related aspects of the use of recombinant DNA techniques are considered, and examples of then-use in the analysis of several human genetic diseases are used to illustrate the biochemical side of genetics. 

Base substitutions and frameshift changes occur spontaneously and can be induced by radiation and chemical mutagens. It is apparent that the molecular mechanisms resulting in these changes are different in each case, but the potential hazards associated with mutagens capable of inducing the different types of mutation are equivalent. 

We now have clear evidence that selenium can be introduced specifically into proteins as selenocysteine and into a subset of tRNA species as mnm Se U or Se2U. The pathways and molecular mechanisms for insertion of selenium into these molecules have been well established in several model systems, the best studied being E. coli. The role for selenium in selenoproteins (i.e., the need for selenium over sulfur) is thought to be its ability to act as a more reactive nucleophile and perhaps a more rapid catalyst. However, a void in our knowledge exists for the specific need for selenium-modified tRNAs. Mutation of either selD or ybbB did not alter the growth characteristics of E. coli- however, no thorough analysis of the bacterial stress response has been carried out in any of these mutants. Clearly, further study is needed to better define the role for selenium in wobble codon usage for a subset of tRNA species. 

These data emphasize the complex nature of the molecular mechanisms controlling polymorphic DPD activity in vivo. The clinical utility for genetic polymorphism testing to date is not optimal because of its low sensitivity and unknown specificity (28). Overall, it can be remarked that the splice site mutation IVS14+1G>A causes severe, even lethal, 5-FU-related toxicity. Unfortunately, the roles of other polymorphisms in the DPYD gene in the severe 5-FU-related toxicity are not clarified. 

Further work on ADH may identify the molecular mechanisms underlying the brain calcification and tonic-clonic seizures associated with the CASR-activating mutations. This information may refine therapy for ADH patients as well as hypoparathyroidism patients who harbor CASR mutations. Further details about ADH can be found in the CASR locus-specific database at http //www.casrdb. mcgill.ca/f4/). 

Yeo, G. S. H., Lank, E. J., Farooqi, I. S., Keogh, J., Challis, B. G., and O RahiUy, S. (2003) Mutations in the human melanocortin-4 receptor gene associated with severe famUial obesity disrupts receptor function through multiple molecular mechanisms. Hum. Mol. Genet. 12, 561-574. 

The primary sequences of important channel peptides, such as the nicotinic acetylcholine receptors, and sodium, potassium, and calcium channels, have been determined by the innovative work of the late professor Numa and his group. " Thereafter, various structural models on the basis of empirical as well as molecular mechanics or molecular dynamics calculations were proposed " and tested by specific point mutation studies. 

The complex of imatinib and other small-molecule ABLl inhibitors as determined by analysis of crystal structures will continue to assist in the development and optimization of inhibitors that are active against mutations conferring resistance in CML (120). The rapidity with which these developments have been occurring is truly astounding and underlies the continued optimism that the treatment of CML and disorders related to it and other disorders where the molecular mechanisms of disease are being unraveled, will become more and more treatable in the future. There is little doubt that combination therapy of CML and related disorders will be a reality in the not-distant future (121). 

Surh, Y. J. 1999. Molecular mechanisms of chemopreventive effects of selected dietary and medicinal phenolic substances. Mutat. Res. Fundam. Mol. Mech. Mutagen. 428 1-2, 305-327. 

Rossman, T.G. (2003) Mechanism of arsenic carcinogenesis an integrated approach. Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis, 533(1-2), 37-65. 

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