U1 small nuclear ribonucleoprotein–pre-messenger RNA complex (U1 snRNP–pre-mRNA) (U1 snRNP–pre-mRNA)

The U1 small nuclear ribonucleoprotein (snRNP)–pre-messenger RNA (pre-mRNA) complex is a critical early intermediate in the eukaryotic pre-mRNA splicing process. It is formed by the base-pairing of the U1 small nuclear RNA (snRNA) with the 5' splice site (5'ss) of an intron, a process supported by a core of Sm proteins and U1-specific proteins such as U1-70K, U1-A, and U1-C (UniProt P08621, P09012, P09234). This complex serves as the primary recognition module for the 5'ss, initiating the assembly of the spliceosome and ensuring the precise removal of introns (PubMed 25529373). In diseases such as Spinal Muscular Atrophy (SMA), mutations in the SMN2 gene weaken the U1 snRNP–5'ss interaction, leading to the exclusion of exon 7 and the production of a truncated, unstable protein (PubMed 29335545). Therapeutic intervention focuses on small molecules that act as splicing modifiers, which bind to the U1 snRNP–pre-mRNA interface to stabilize the complex and promote exon inclusion (PubMed 32531193). These drugs, including Risdiplam and Branaplam, represent a novel class of molecular glues that target RNA-protein interactions to correct genetic defects.

Other names

U1 snRNP–5' splice site complexU1 snRNP–SMN2 pre-mRNA complexU1 small nuclear ribonucleoprotein complexU1 snRNP–5'ss complex

Small molecule splicing modifiers act as molecular glues to stabilize the transient interaction between the U1 snRNP and the 5' splice site of specific pre-mRNAs, thereby promoting the inclusion of exons that would otherwise be skipped due to weak splice site recognition.