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Published August 2014 | Published + Supplemental Material
Journal Article Open

Exquisite Sequence Selectivity with Small Conditional RNAs


Dynamic RNA nanotechnology based on programmable hybridization cascades with small conditional RNAs (scRNAs) offers a promising conceptual framework for engineering programmable conditional regulation in vivo. While single-base substitution (SBS) somatic mutations and single-nucleotide polymorphisms (SNPs) are important markers and drivers of disease, it is unclear whether synthetic RNA signal transducers are sufficiently programmable to accept a cognate RNA input while rejecting single-nucleotide sequence variants. Here, we explore the limits of scRNA programmability, demonstrating isothermal, enzyme-free genotyping of RNA SBS cancer markers and SNPs using scRNAs that execute a conditional hybridization cascade in the presence of a cognate RNA target. Kinetic discrimination can be engineered on a time scale of choice from minutes to days. To discriminate even the most challenging single-nucleotide sequence variants, including those that lead to nearly isoenergetic RNA wobble pairs, competitive inhibition with an unstructured scavenger strand or with other scRNAs provides a simple and effective principle for achieving exquisite sequence selectivity.

Additional Information

© 2014 American Chemical Society. ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Received: April 29, 2014. Revised: June 19, 2014. Published: June 30, 2014. We thank V. A. Beck for helpful discussions. This work was funded by the National Institutes of Health (NIH 5R01CA140759), the National Science Foundation via the Molecular Programming Project (NSF-CCF-0832824 and NSF-CCF-1317694), the Gordon and Betty Moore Foundation (GBMF2809), and the Elsa U. Pardee Foundation.

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Published - nl501593r.pdf

Supplemental Material - nl501593r_si_001.pdf


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