Small Molecule Targeted Recruitment of a Nuclease to RNA
Open accessAbstract
The choreography between RNA synthesis and degradation is a key determinant in biology. Engineered systems such as CRISPR have been developed to rid a cell of RNAs. Here, we show that a small molecule can recruit a nuclease to a specific transcript, triggering its destruction. A small molecule that selectively binds the oncogenic microRNA(miR)-96 hairpin precursor was appended with a short 2'-5' poly(A) oligonucleotide. The conjugate locally activated endogenous, latent ribonuclease (RNase L), which selectively cleaved the miR-96 precursor in cancer cells in a catalytic and sub-stoichiometric fashion. Silencing miR-96 derepressed pro-apoptotic FOXO1 transcription factor, triggering apoptosis in breast cancer, but not healthy breast, cells. These results demonstrate that small molecules can be programmed to selectively cleave RNA via nuclease recruitment and has broad implications.
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Incorporation of RNA-binding small molecules into a heterobifunctional design has afforded RIBOTACs that induce proximity between an RNA of interest and a ribonuclease to prompt RNA degradation.
“Moreover, incorporation of RNA-binding small-molecules into a heterobifunctional design has afforded ribonuclease targeting chimeras (RIBOTACs): small molecules that induce proximity between an RNA of interest and a ribonuclease to prompt RNA degradation.37−39”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [37]
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- Authors
- Costales, M. G., Matsumoto, Y., Velagapudi, S. P., & Disney, M. D.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Disney, Matthew D.
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-05-24
- Volume
- 140
- Issue
- 22
- Pages
- 6741-6744
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC6100793
- OpenAlex
- W4247897378
- Cited by
- 212
- References
- 14
- Citations by year
- 2026: 18 · 2025: 29 · 2024: 37 · 2023: 35 · 2022: 27 · 2021: 16 · 2020: 32 · 2019: 16 · 2018: 1 · 2014: 1
- FWCI
- 5.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (5R01GM097455)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- ribonuclease L, miR-96, RNA degradation, FOXO1, apoptosis, breast cancer
- MeSH terms
- Endoribonucleases, Molecular Structure, MicroRNAs, Small Molecule Libraries
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