essenger RNAs are typically thought of as passive carriers of genetic information that are acted upon by protein- or small RNA-regulatory factors and by ribosomes during the process of translation. Recently, we have found that the 5'-untranslated regions (UTRs) of numerous bacterial mRNAs serve a more proactive role in metabolic monitoring and genetic control. RNA genetic switches called riboswitches selectively bind metabolites without the need for proteins, and subsequently modulate gene expression by several distinct mechanisms. Riboswitches exhibit striking complexity in structure and action, and our findings indicate that cells from all three domains of life use these metabolite-sensing RNAs to control fundamental metabolic pathways. Furthermore, we have evidence that riboswitches or their components sometimes occur in tandem and that these arrangements lead to even greater gene control sophistication. We propose to continue our efforts to establish the basic features of new-found classes of riboswitches, with particular emphasis on the characterization of two novel classes that bind cyclic di-GMP and tetrahydrofolate. These analyses of the structural and functional characteristics of novel riboswitch systems are intended to establish the basic principles of riboswitch molecular recognition and function. Our findings will increase our understanding of bacterial gene control mechanisms, facilitate atomic-resolution structural analyses of riboswitch RNAs, and provide possible new targets for antimicrobial drug development.

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We propose to establish the detailed mechanisms by which at least two riboswitch classes in bacteria bind ligands and control the expression of genes involved in coenzyme and second messenger metabolism. A series of biochemical and genetic techniques will be applied to establish molecular recognition characteristics of the riboswitch aptamers and the mechanisms for gene control used by the adjoining expression platforms

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Yale University
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