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.

Public Health Relevance

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)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BCMB-K)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
New Haven
United States
Zip Code
Li, Sanshu; Breaker, Ronald R (2017) Identification of 15 candidate structured noncoding RNA motifs in fungi by comparative genomics. BMC Genomics 18:785
Nelson, James W; Atilho, Ruben M; Sherlock, Madeline E et al. (2017) Metabolism of Free Guanidine in Bacteria Is Regulated by a Widespread Riboswitch Class. Mol Cell 65:220-230
Reiss, Caroline W; Strobel, Scott A (2017) Structural basis for ligand binding to the guanidine-II riboswitch. RNA 23:1338-1343
Wang, Jimin; Moore, Peter B (2017) On the interpretation of electron microscopic maps of biological macromolecules. Protein Sci 26:122-129
Wang, Jimin; Askerka, Mikhail; Brudvig, Gary W et al. (2017) Insights into Photosystem II from Isomorphous Difference Fourier Maps of Femtosecond X-ray Diffraction Data and Quantum Mechanics/Molecular Mechanics Structural Models. ACS Energy Lett 2:397-407
Nelson, James W; Breaker, Ronald R (2017) The lost language of the RNA World. Sci Signal 10:
Lomakin, Ivan B; Stolboushkina, Elena A; Vaidya, Anand T et al. (2017) Crystal Structure of the Human Ribosome in Complex with DENR-MCT-1. Cell Rep 20:521-528
Wang, Jimin; Askerka, Mikhail; Brudvig, Gary W et al. (2017) Crystallographic Data Support the Carousel Mechanism of Water Supply to the Oxygen-Evolving Complex of Photosystem II. ACS Energy Lett 2:2299-2306
Greenlee, Etienne B; Stav, Shira; Atilho, Ruben M et al. (2017) Challenges of Ligand Identification for the Second Wave of Orphan Riboswitch Candidates. RNA Biol :0
Arachchilage, Gayan Mirihana; Sherlock, Madeline E; Weinberg, Zasha et al. (2017) SAM-VI RNAs Selectively Bind S-adenosylmethionine and Exhibit Similarities to SAM-III Riboswitches. RNA Biol :0

Showing the most recent 10 out of 126 publications