COULD TRANSCRIPTION INDUCED MUTATIONS CAUSE CANCER?

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DESCRIPTION: (Adapted from the investigator's abstract) There may be a connection between malnutrition, transcription, mutations and cancer. In mammals, a number of genes are derepressed in response to caloric restrictions, and amino acid limitation can also induce gene expression, which increases mutation rates. In a model system, the effect of transcription (activated by guanosine tetraphosphate, or ppGpp) on mutation rates and mutations in the leu operon of E. coli will be examined. Specific aims are to determine the: A. Kinetics of mRNA turnover during logarithmic growth and during leucine starvation. B. Effect of ppGpp on the kinetics of transcription initiation in leuB and pyrD. C. Effect of antisense RNA and DNA on leuB. The proposed investigations have implications for understanding mechanisms of mutations and cancer. It is estimated that the majority of cancers are caused by environmental (including nutritional) conditions. Data indicate that transcription can enchance the rate of both point mutations and frameshifts, suggesting that genetic derepression may be a major cause of background mutations. If so, this mechanism provides the critical link to metabolic activities evoked by malnutrition, and could play a role in directing which mutations occur. Basic research on the vulnerability of single-stranded DNA to mutation and repair may well reveal insights into the mechanisms of tumorgenesis, and thus aid in the prevention or treatment of cancer.