The U1 snRNP-specific protein U1C is a key regulator of SMN complex-mediated snRNP formation.

The stability and abundance of spliceosomal small nuclear ribonucleoproteins (snRNPs) are determined by the assembly of an Sm protein ring (Sm core) on each snRNA, a process orchestrated by the survival of motor neurons (SMN) complex. While the role of the SMN complex as a chaperone is well-established, the mechanisms that regulate its activity remain poorly understood. In this study, we identify U1C, a U1 snRNP-specific protein, as a key regulator of the SMN complex. Using in vitro Sm core assembly and protein binding assays, we demonstrate that U1C is essential for Sm core assembly on all snRNAs. In the absence of U1C, Sm core formation on U1 snRNA is disrupted, impairing the SMN complex's ability to facilitate Sm core assembly on other snRNAs. Furthermore, we show that U1C interacts with the SMN complex via post-translational arginine methylations at its C-terminal region, a site distinct from its interaction with U1-70K. Notably, we demonstrate that a prevalent cancer-associated mutation in U1 snRNA, located near the U1C binding site, not only disrupts Sm core assembly but also sequesters the SMN complex, thereby inhibiting canonical snRNP formation. These findings provide important mechanistic insights into how snRNP-specific proteins regulate the SMN complex and suggest that U1 snRNA mutations in numerous cancers may contribute to dysregulation of RNA metabolism by impairing SMN complex activity.