Document Detail


Reengineering orthogonally selective riboswitches.
MedLine Citation:
PMID:  20133756     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The ability to independently control the expression of multiple genes by addition of distinct small-molecule modulators has many applications from synthetic biology, functional genomics, pharmaceutical target validation, through to gene therapy. Riboswitches are relatively simple, small-molecule-dependent, protein-free, mRNA genetic switches that are attractive targets for reengineering in this context. Using a combination of chemical genetics and genetic selection, we have developed riboswitches that are selective for synthetic "nonnatural" small molecules and no longer respond to the natural intracellular ligands. The orthogonal selectivity of the riboswitches is also demonstrated in vitro using isothermal titration calorimetry and x-ray crystallography. The riboswitches allow highly responsive, dose-dependent, orthogonally selective, and dynamic control of gene expression in vivo. It is possible that this approach may be further developed to reengineer other natural riboswitches for application as small-molecule responsive genetic switches in both prokaryotes and eukaryotes.
Authors:
Neil Dixon; John N Duncan; Torsten Geerlings; Mark S Dunstan; John E G McCarthy; David Leys; Jason Micklefield
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-01-26
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  107     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-02-17     Completed Date:  2010-05-10     Revised Date:  2013-05-31    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2830-5     Citation Subset:  IM    
Affiliation:
School of Chemistry and Manchester Interdisciplinary Biocentre, The University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom.
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MeSH Terms
Descriptor/Qualifier:
Aptamers, Nucleotide / metabolism
Calorimetry
Crystallography, X-Ray
Gene Expression Regulation / physiology*
Genetic Engineering / methods*
Models, Molecular*
Molecular Structure
RNA, Catalytic / metabolism*
RNA, Messenger / metabolism*
Grant Support
ID/Acronym/Agency:
BB/D005612/1//Biotechnology and Biological Sciences Research Council
Chemical
Reg. No./Substance:
0/Aptamers, Nucleotide; 0/RNA, Catalytic; 0/RNA, Messenger
Comments/Corrections

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