U1 snRNP-Specific U1C Acts as the Gatekeeper of the Survival of Motor Neurons (SMN) Complex in snRNP Biogenesis

SUMMARY The stability and abundance of spliceosomal snRNPs are determined by the assembly of an Sm protein ring (Sm core) on each snRNA, a process facilitated by the survival of motor neuron (SMN) complex. Whereas the SMN complex’s role as a chaperone is well-established, the mechanisms that regulate its activity remain unclear. Our study identifies U1C, a U1 snRNP-specific protein, as a key regulator of the SMN complex. U1C together with U1-70K facilitates U1 snRNP formation, rendering the SMN complex accessible for other snRNAs to assemble Sm cores. Remarkably, a prevalent cancer-associated mutation in U1 snRNA near the U1C binding site not only disrupts Sm core assembly but also sequesters the SMN complex, inhibiting canonical snRNP formation. Our findings provide mechanistic insights into how snRNP-specific proteins regulate the SMN complex and suggest that U1 snRNA mutations in numerous cancers disrupt the SMN complex, leading to perturbation in various RNA metabolism pathways. Highlights U1C facilitates the formation of Sm core not only on U1 snRNA but also on other snRNAs. U1C together with U1-70K promotes U1 snRNP formation, enabling the SMN complex to recruit Gemin5/other snRNAs complex. The divalent binding of U1C to the SMN complex is mediated by U1C’s N-terminus helix, interacting with U1-70K, and its arginine-methylated C-terminus domain, binding to the SMN protein. Multiple U1 snRNA mutations in cancer patients defect in Sm core assembly and potentially sequester the SMN complex, thereby inhibiting canonical snRNP formation.