It has recently become a matter of importance to understand the molecular basis of frameshift mutation and frameshift suppression in eucaryotes. Current interest in this subject may be attributed to the work of Ames, who has shown that frameshift mutations induced in Salmonella by the acridine half-mustards (ICR compounds) revert at high frequency in the presence of compounds known to be carcinogenic in animals. Using the frequency of reversion as the criterion for mutagenic activity, Ames has developed a sensitive test system for screening compounds suspected as being environmental mutagens and therefore harmful to the general public. The major conclusions from this work support the mutation theory of carcinogenesis, since most compounds which are carcinogenic in animals are also mutagenic in Salmonella. It is of interest to determine whether animal carcinogens which are mutagenic in procaryotes are also mutagenic in eucaryotes. The basis for this determination lies in the characterization of frameshift mutations induced by specific compounds in a eucaryotic organism which is amenable to genetic manipulation. The yeast Saccharomyces cerevisiae is ideally suited for this purpose. Evidence from this laboratory indicates that the acridine half-mustard ICR-170 induces frameshift mutations in yeast. Furthermore, frameshift-specific suppressors have been isolated by reverting these mutations and the suppressors have been identified in some cases as structural alterations in specific transfer RNAs. The availability of cloned DNA fragments containing suppressible frameshift mutations and suppressor genes will enable the precise molecular analysis of this system of interacting genes. In addition, the suppressors can be modified in terms of their expression by mutations which may affect the regulation and synthesis of transfer RNA. Thus, this system provides a way to examine frameshift mutagenesis and its relationship to carcinogenesis, a direct in vivo genetic approach to the analysis of genetic decoding interactions and mechanisms of mRNA translation in eucaryotes, and gene regulation through the analysis of transfer RNAs involved in frameshift suppression.
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