A Molecular Clamp Targeting the TOE1:Sm Complex Imparts Tunable Regulation of Splicing

Small nuclear RNAs (snRNAs) are required for the structure and function of the spliceosome. The RNA exonuclease TOE1 trims and matures the 3’ ends of snRNAs, but how this post-transcriptional process contributes to spliceosome activity remains poorly understood. Here we report a potent and selective covalent ligand that targets TOE1 specifically when bound to the Sm complex. We find that this compound acts as a “molecular clamp”, dramatically stabilizing TOE1 interactions with the Sm complex and triggering excessive trimming of snRNA 3’ termini in cells. We show that this over-trimming activity is tunable by factors that include the expression levels of TOE1 and auxiliary splicing regulators like SNRPB2, which create synthetic lethality interactions with TOE1 ligands that alter splicing and impair cancer cell growth. Our findings demonstrate the feasibility of chemically modulating spliceosome function through targeting the processing of its snRNA components, which may have broad therapeutic implications for splicing-related diseases.