Riboswitches are structured RNA domains commonly located in the 52 untranslated regions (UTRs) of messenger RNAs where they selectively bind target metabolites and regulate gene expression. We have discovered a fluoride-responsive riboswitch class which offers an unprecedented opportunity to establish the molecular basis for fluoride toxicity and its alleviation in organisms distributed among two of the three domains of life. Of particular interest is the study of fluoride riboswitches from bacterial species because of the likely implications for understanding the health effects of fluoride additives in water and dental hygiene products. We seek to provide a strong biochemical and genetic foundation for understanding how fluoride ions are sensed by many species and what genetic consequences occur when cells detect dangerous levels of this anion. Moreover, our experiments are designed to produce data that empowers other researchers who wish to conduct studies that elucidate the molecular basis of fluoride toxicity, anti-caries efficacy, and bacterial responses to fluoride exposure. We will conduct bioinformatics searches to discover additional fluoride- sensing RNAs, examine the biochemical and genetic functions of known and new-found fluoride riboswitches, and examine the function of gene products whose expression is regulated by fluoride. This knowledge will help assess the long-standing hypothesis that the antibacterial activity of fluoride contributes to the prevention of dental caries.

Public Health Relevance

Fluoride is widely used as an additive to drinking water and oral hygiene products due to its efficacy in preventing tooth decay. Among the proposed mechanisms of fluoride action is its antibacterial activity at high concentrations in dental plaque We have discovered a novel fluoride sensing system in microorganisms that provides extraordinary opportunities to understand and exploit fluoride toxicity in bacteria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE022340-02
Application #
8510625
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
2012-07-13
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$359,640
Indirect Cost
$143,640
Name
Yale University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Nelson, James W; Zhou, Zhiyuan; Breaker, Ronald R (2014) Gramicidin D enhances the antibacterial activity of fluoride. Bioorg Med Chem Lett 24:2969-71
Nelson, James W; Sudarsan, Narasimhan; Furukawa, Kazuhiro et al. (2013) Riboswitches in eubacteria sense the second messenger c-di-AMP. Nat Chem Biol 9:834-9