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J Am Chem Soc. 2018 Jun 6;140(22):6741-6744. doi: 10.1021/jacs.8b01233. Epub 2018 May 24.

Small Molecule Targeted Recruitment of a Nuclease to RNA.

Author information

1
The Department of Chemistry , The Scripps Research Institute , Jupiter , Florida 33458 , United States.

Abstract

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.

PMID:
29792692
PMCID:
PMC6100793
DOI:
10.1021/jacs.8b01233
[Indexed for MEDLINE]
Free PMC Article

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