Uridine-rich non-coding RNAs of 100 to 300 nucleotides confined to the nucleus, where they assemble with Sm or LSm proteins into small nuclear ribonucleoproteins (snRNPs) to form the catalytic and substrate-recognition heart of the spliceosome. By base-pairing directly to intron boundaries and folding into a divalent-metal-ion catalytic center, spliceosomal snRNAs excise non-coding introns and ligate coding exons across nearly all human messenger RNA precursors.
Target of splice-switching ASOs (nusinersen in SMA); autoantigen target in systemic lupus erythematosus (anti-Sm/anti-U1 RNP)
Structure & Biogenesis
The major spliceosomal snRNAs — U1, U2, U4, and U5 — are transcribed in the nucleus by RNA polymerase II with a 5' monomethylguanosine cap, exported transiently to the cytoplasm where the SMN (survival motor neuron) complex loads a seven-member ring of Sm proteins onto a conserved uridine-rich Sm-binding site, hypermethylated at the 5' cap to 2,2,7-trimethylguanosine (TMG), and re-imported into the nucleus.
By contrast, U6 and U6atac snRNAs are transcribed by RNA polymerase III, never leave the nucleus, receive a 5' γ-monomethylphosphate cap, and bind a heptameric LSm2–8 protein ring at their uridine-rich 3' tail.
Within nuclear Cajal bodies, newly assembled snRNAs undergo site-specific 2'-O-methylation and pseudouridylation guided by Cajal body-specific small nucleolar RNAs (scaRNAs).
Mechanism of Action
As detailed in Cindy Will and Reinhard Lührmann's structural and functional synthesis of the spliceosome (2011), splicing proceeds through stepwise RNA–RNA rearrangements: U1 snRNA base-pairs to the 5' splice site (GU) of the pre-mRNA intron, while U2 snRNA base-pairs around the branch-point adenosine, bulging it out for nucleophilic attack. Recruitment of the U4/U6.U5 tri-snRNP is followed by ATP-dependent helicase unwinding of U4 from U6; U6 snRNA then displaces U1 at the 5' splice site and base-pairs with U2 snRNA to fold into an active ribozyme that coordinates two catalytic magnesium ions — structurally and mechanistically homologous to self-splicing Group II introns — to execute both transesterification steps (lariat formation and exon ligation).
Biological & Regulatory Roles
Alternative splice-site selection across more than 90% of multi-exon human genes generates tissue-specific protein isoforms, exemplified by alternative splicing of the CALCA transcript into thyroid calcitonin versus neuronal CGRP.
Beyond the spliceosome, U7 snRNA directs 3'-end processing of non-polyadenylated replication-dependent histone pre-mRNAs, and 7SK snRNA sequesters P-TEFb to regulate RNA polymerase II pause release.
Interactions & Complexes
Associates dynamically with over 150 spliceosomal proteins, SR proteins, and nuclear lncRNAs such as MALAT1 in nuclear speckles before mature mRNA is exported to the ribosome.
Therapeutic & Biotechnology Applications
Loss of the SMN1 protein impairs snRNP assembly and causes spinal muscular atrophy (SMA); the FDA-approved antisense oligonucleotide nusinersen blocks an intronic splicing silencer in SMN2 pre-mRNA so the spliceosome includes exon 7.
Autoantibodies against Sm proteins and the U1 snRNP complex (anti-Sm and anti-RNP) produced by immune B cells are diagnostic hallmarks of systemic lupus erythematosus and mixed connective tissue disease.
Sources
Spliceosome Structure & Mechanism Review: Will CL, Lührmann R. Spliceosome structure and function. Cold Spring Harb Perspect Biol. 2011;3(7):a003707. PMID 21441581.