A Toxic RNA Catalyzes the Cellular Synthesis of Its Own Inhibitor, Shunting It to Endogenous Decay Pathways. Issue 2 (20th February 2020) - Benhamou, Raphael I.
Summary: Myotonic dystrophy type 2 (DM2) is a genetically defined disease caused by a toxic expanded repeat of r(CCUG) [r(CCUG) exp ], harbored in intron 1 of CCHC-type zinc-finger nucleic acid binding protein ( CNBP ) pre-mRNA. This r(CCUG) exp causes toxicity via a gain-of-function mechanism, resulting in three pathological hallmarks: aggregation into nuclear foci; sequestration of muscleblind-like-1 (MBNL1) protein, leading to splicing defects; and retention of CNBP intron 1. We studied two types of small molecules with different modes of action, ones that simply bind and ones that are templated by r(CCUG) exp in cells, i.e., the RNA synthesizes its own drug. Indeed, our studies completed in DM2 patient-derived fibroblasts showed that the compounds disrupt the r(CCUG) exp -MBNL1 complex, reduce intron retention, subjecting the liberated intronic r(CCUG) exp to native decay pathways, and rescue other DM2-associated cellular defects. Importantly, this study shows that small molecules can modulate RNA biology by shunting toxic transcripts toward native decay pathways. Graphical Abstract: Highlights: RNA repeat expansions can cause intron retention by binding proteins Small molecules that bind RNA repeats and inhibit protein binding trigger decay A toxic RNA repeat can catalyze the synthesis of its own inhibitor on-site On-site drug synthesis most potently affects repeat expansion disease biology Abstract : RNA repeat expansions cause >30 diseases, and both oligonucleotides and small molecules have been developed to inhibit their dysfunction. Benhamou et al. show for the first time that small molecules targeting structured, disease-causing RNAs can shunt them toward native decay pathways by affecting their processing.