A small molecule that binds an RNA repeat expansion stimulates its decay via the exosome complex
| Autor: | Alicia J. Angelbello, Albert S. Jun, Zhen Zhi Tang, Madhuparna Roy, Shruti Choudhary, Matthew D. Disney, Kye Won Wang, Suzanne G. Rzuczek, Raphael I. Benhamou, Ilyas Yildirim, Charles A. Thornton, Jonathan L. Chen |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Untranslated region congenital hereditary and neonatal diseases and abnormalities Exosome complex Clinical Biochemistry Biology Exosomes 01 natural sciences Biochemistry Small Molecule Libraries 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Drug Discovery Humans Myotonic Dystrophy Molecular Biology Cells Cultured 030304 developmental biology Pharmacology 0303 health sciences Messenger RNA 010405 organic chemistry Oligonucleotide Fuchs' Endothelial Dystrophy Intron RNA Small molecule 0104 chemical sciences Cell biology chemistry RNA splicing Molecular Medicine Female Trinucleotide Repeat Expansion Trinucleotide repeat expansion Exosome Multienzyme Ribonuclease Complex 030217 neurology & neurosurgery DNA |
| Popis: | We describe the design of a small molecule that binds the structure of a r(CUG) repeat expansion [r(CUG)exp] and reverses molecular defects in two diseases mediated by the RNA - myotonic dystrophy type 1 (DM1) and Fuchs endothelial corneal dystrophy (FECD). Thus, a single structure-specific ligand has potential therapeutic benefit for multiple diseases, in contrast to oligonucleotide-based modalities that are customized for each disease by nature of targeting the gene that harbors the repeat. Indeed, the small molecule binds the target with nanomolar affinity and >100-fold specificity vs. many other RNAs and DNA. Interestingly, the compound’s downstream effects are different in the two diseases, owing to the location of the repeat expansion. In DM1, r(CUG)exp is harbored in the 3’ untranslated region (UTR) of and mRNA, and the compound has no effect on the RNA’s abundance. In FECD, however, r(CUG)exp is located in an intron, and the small molecule, by binding the repeat expansion, facilitates excision of the intron, which is then degraded by the exosome complex exonuclease, hRRP6. Thus, structure-specific, RNA-targeting small molecules can act disease-specifically to affect biology, either by disabling its gain-of-function mechanism (DM1) or by stimulating quality control pathways to rid a disease-affected cell of a toxic RNA (FECD).Significance statementMany different diseases are caused by toxic structured RNAs. Herein, we designed a lead small molecule that binds a toxic structure and rescues disease biology. We show that a structure-specific small molecule can improve disease-associated defects in two diseases that share the common toxic RNA structure. In one disease, the toxic structure is harbored in an intron and causes its retention. The compound facilitates processing of a retained intron, enabling the disease-affected cell to remove the toxic RNA. |
| Databáze: | OpenAIRE |
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