Section on Molecular Regulation

Head: Charles M. Cashel

 We wish to understand how nutrient availability coordinates bacterial genomic expression. Within this broad goal, we continue to focus on the roles of two regulatory analogues of GTP and GDP that are modified with ribose 3′ pyrophosphates and collectively termed ppGpp. Remarkably, nutrient limitation elevates levels of the ppGpp nucleotides regardless of whether the organism is starved for sources of amino acids, phosphate, nitrogen, carbon, or iron. Only some of a bacterium’s sensing mechanisms are currently understood. Signaling roles are assigned to ppGpp because the elimination of ppGpp during starvation can abolish regulation and lead to difficulties in surviving starvation. Conversely, elevating ppGpp without starvation can mimic aspects of starvation. Recent work has revealed that transcription regulation by ppGpp requires the cofactor DksA, a structural homologue of the GreA and GreB elongation transcription factors. This year, we used genetic screens with multicopy gene fragment libraries to look for genes that complement ppGpp-deficiency (ppGpp0) phenotypes. Our approach revealed new candidates and possibly new mechanisms in the (p)ppGpp-DksA-GreA–regulatory network. Motility regulation studies unexpectedly disclosed involvement of GreA in this network. We are continuing to work on intermediary metabolism mutants to learn why they are (p)ppGpp0 synthetic lethals.

Resources

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• E-Mail the Lab: cashel@box-c.nih.gov
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