New Functions of Riboswitches

by Lee, Elaine Renee, Ph.D., YALE UNIVERSITY, 2010, 208 pages; 3440596

Abstract:

Riboswitches are gene control elements usually located in the 5' untranslated regions of messenger RNAs in bacteria, plants, and fungi. Composed of two parts, the aptamer forms a structured pocket that binds ligands and the expression platform modulates the expression of associated genes depending on whether ligand is bound to the aptamer.

Researchers have begun to study riboswitches as potential antibiotic drug targets in part because other non-coding RNAs have been shown to be effective targets. Riboswitches in bacteria are often located upstream of genes that synthesize the ligand to which they bind. Thus, it may be possible to find compounds that can turn off the biosynthesis of essential metabolic genes upon binding to riboswitches. Roseoflavin, an analog of flavin mononucleotide (FMN), has been known for decades to have antibiotic properties, but the mechanism underlying its toxicity has remained unknown. I recently showed that roseoflavin binds to FMN riboswitches and that reporter genes controlled by FMN riboswitches are down-regulated in the presence of roseoflavin. These results suggest that the toxicity of roseoflavin involves its ability to bind directly to FMN riboswitches.

As new genomes are sequenced, more riboswitch classes are being identified using bioinformatics searches. A class of riboswitches that binds to S-adenosylhomocysteine was identified that regulates genes involved in the S-adenosylmethionine recycling metabolic pathway. Two classes of riboswitches that bind to cyclic di-GMP, a second messenger in bacteria that regulates biofilm formation, were also found and the identification of two distinct riboswitch classes that bind to cyclic di-GMP helps explain some of the mystery surrounding gene regulation by the second messenger. Interestingly, one example of a cyclic di-GMP-II riboswitch is located immediately upstream of a group I intron and the presence of the second messenger stabilizes a base-pairing element immediately downstream of the riboswitch that allows the first GTP attack in the group I intron mechanism to occur in this P1 stem. In the absence of cyclic di-GMP, GTP attack occurs downstream near the 3' splice site. Thus, cyclic di-GMP appears to regulate a group I intron and may be the first example of a naturally occurring allosteric ribozyme.

AdvisersRonald R. Breaker; Nicholas Ornston
SchoolYALE UNIVERSITY
Source TypeDissertation
SubjectsMolecular biology; Biochemistry
Publication Number3440596

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