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R. L1.404 5323 Harry Hines Blvd. Dallas, TX 75390-9038 Phone: 214-648-9114 Fax: 214-648-8856 E-mail: Wade.winkler@utsouthwestern.edu 2005 Searle Scholar |
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RNA
Functions and the Posttranscriptional Control of Bacterial Gene
Expression-- All organisms must regulate the expression of their genes temporally, quantitatively, functionally, and oftentimes, spatially. Additionally, these regulatory processes must be responsive to a wide variety of chemical and physical cues. Exploration of the full range of regulatory possibilities and the biochemical mechanisms that they utilize will reveal the interconnectedness of metabolic pathways and elucidate life’s underlying genetic circuitry. Regulation of gene expression can occur through an alteration in any one of the steps that occur along the information processing pathways. Although control of transcription initiation is presumed to be the predominate mode of gene expression control, there is a growing appreciation for posttranscriptional regulatory mechanisms. Our laboratory is interested in the genetic and biochemical characterization of these regulatory strategies, as well as the discovery of novel regulatory mechanisms. We are using this data to develop biological engineering techniques that will be used for a variety of biomedical applications, including the development of novel drugs.
Recent data indicate that, in bacteria, posttranscriptional regulatory strategies often employ specific RNA structures termed riboswitches, which are embedded within the 5’ untranslated region of mRNAs. These RNA sequences fold into specific three-dimensional shapes that act as molecular receptors for certain intracellular metabolites. Upon binding of the metabolite there is a change in conformation that ultimately results in a change in gene expression. Switching between conformations can influence mRNA stability, efficiency of translation initiation, or in some cases, the processivity of RNA polymerase. Riboswitches are widespread throughout biology and are utilized for genetic control over many fundamental genes. For these and other reasons, we are interested in exploring the biochemistry, biological distribution, and biomedical applications of riboswitch RNAs. We are particularly interested in a riboswitch that harnesses the self-cleavage ability of a ribozyme in order to regulate expression of a bacterial gene, glmS. We are working to uncover the molecular details for the novel mechanism by which this cleavage event results in a change in gene expression.
When considering the assorted range of
functions accomplished by RNAs in biology one has to consider more
than just cis-acting RNA structures like riboswitches. RNAs are also
involved in modification of other nucleic acids, as unstructured
regulatory oligonucleotides, and as structured trans-acting
regulatory RNAs. And this partial list may be just the beginning.
Several billion years ago, organisms with surprisingly complex
metabolisms were likely to have relied upon specific classes of RNAs
for all of their genomic and catalytic requirements. Therefore,
given the extensive precedence for present or past roles of RNA
polymers, there is no reason not to expect that modern organisms are
replete with biological RNAs enacting functions other than that of
the ’passive mRNA’ transcript. Our lab is interested in
discovering just how often, and in what capacity, these interesting
and important RNA sequences are utilized inside a given cell. |
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