Small Molecule Targeted Recruitment of a Nuclease to RNA.
Matthew G CostalesYasumasa MatsumotoSai Pradeep VelagapudiMatthew D DisneyPublished in: Journal of the American Chemical Society (2018)
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.
Keyphrases
- small molecule
- transcription factor
- cell proliferation
- long non coding rna
- dna binding
- cell cycle arrest
- protein protein
- long noncoding rna
- cell death
- pi k akt
- induced apoptosis
- endoplasmic reticulum stress
- cancer therapy
- oxidative stress
- anti inflammatory
- single cell
- genome wide
- rna seq
- signaling pathway
- cell therapy
- crispr cas
- gene expression