Restoration of Ribozyme Tertiary Contact and Function by Using a Molecular Glue for RNA |
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| Authors: | Dr. Chikara Dohno Maki Kimura Prof. Kazuhiko Nakatani |
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| Affiliation: | Department of Regulatory Bioorganic Chemistry, The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka, Japan |
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| Abstract: | Some RNA classes require folding into the proper higher‐order structures to exert their functions. Hammerhead ribozyme (HHR) requires a folding conformation stabilized by tertiary interaction for full activity. A rationally engineered HHR was developed that was inactive, but could be activated by a synthetic RNA‐binding ligand, naphthyridine carbamate tetramer with Z‐stilbene linker (Z‐NCTS). Binding of Z‐NCTS could induce the formation of an active folding structure and thereby restore ribozyme activity, where Z‐NCTS acts as a molecular glue to bring two isolated RNA loops into contact with each other. Next, we designed a Z‐NCTS‐responsive genetic switch using the HHR sequence inserted into the 3′ untranslated region as a cis‐acting element. We demonstrated that the rationally designed ribozyme switch enabled regulation of gene expression by Z‐NCTS and was functional in mammalian cells. |
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| Keywords: | aptazyme molecular glue riboswitch ribozymes RNA |
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