Abstract 2106 A U1 snRNP-specific U1C Acts as the Gatekeeper of the SMN Complex, Regulating snRNP Repertoire

Small nuclear ribonucleoprotein particles (snRNPs) are major components in spliceosomes that play critical roles in post-transcriptional gene regulation. Among these, U1 snRNP is an abundant non-coding RNA-protein complex that plays critical roles in pre-mRNA splicing as well as preventing premature termination of nascent transcripts (telescripting). Therefore, ensuring sufficient and precise repertoire of snRNPs is essential for the function of U1 snRNP in protein-coding gene expression. The abundance of snRNPs is determined by the assembly of an Sm protein ring on snRNA (Sm core), and this process is facilitated by the SMN complex. However, the mechanism through which the SMN complex, acting as an RNA-Protein complex chaperone, regulates snRNP repertoire remains unknown. Here, we find that the U1 snRNP-specific U1C protein functions as a gatekeeper of the SMN complex by assisting U1 and other snRNPs formation. By employing in vitro Sm core assembly and biochemical methods, we identified that U1C plays a role in releasing U1 snRNP from the SMN complex. This makes the complex available for the association of Gemin5, an essential snRNA binding protein for other snRNAs. Moreover, the U1 snRNA mutations near the U1C binding site identified in cancer patients not only disrupt Sm core assembly but also sequester the SMN complex, impeding the formation of canonical snRNPs. Our findings provide mechanistic insights into how U1 snRNP-specific proteins regulate the abundance and repertoire of snRNPs. Furthermore, they suggest that mutations in U1 snRNA observed in cancers potentially disrupt the SMN complex's association with numerous RNA binding proteins, leading to perturbation in the metabolism of various RNAs. This work is supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R15GM152936 and and by the University of Texas Arlington start-up funds.