Many years ago, Mike Cashel's Section on Molecular Regulation discovered the guanine nucleotide analog ppGpp, found many years ago to function as a second messenger in bacteria and plants, where it couples global regulation of gene expression to nutrient availability. Recently, another laboratory discovered that worms, flies, and humans have genes for highly specific, structural homologs of bacterial ppGpp hydrolases. This raises the question as to whether ppGpp itself is present in animals, where ppGpp is exceedingly difficult to detect biochemically. Therefore, the group is embarking on a search for an animal ppGpp synthetase by screening cDNA developmental libraries from fruit flies for genes that complement growth defects of bacterial ppGpp mutants. The presence of ppGpp seems likely because either deletion of the fly hydrolase or overexpression of a bacterial ppGpp synthetase similarly regulate fly development and global gene expression in a manner reminiscent of ppGpp behavior in lower organisms. The Section also has a special interest in the details of bacterial mechanisms by which ppGpp either activates or inhibits RNA polymerase transcription of specific promoters. These effects are based upon intrinsic kinetic properties of specific promoters, without the help of sequence recognition proteins. The studies are important because ppGpp is necessary for virulence-gene expression in most bacterial pathogens.
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