Language
English
Publication Date
11-2-2026
Journal
Genes Development
DOI
10.1101/gad.353690.126
PMID
42562572
PMCID
PMC13573567
PubMedCentral® Posted Date
11-1-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Defective small nuclear (sn)RNAs are produced from hundreds of human snRNA pseudogenes and mutant snRNA genes associated with human developmental disorders. Machineries that prevent defective snRNAs from disrupting pre-mRNA splicing remain poorly defined. Here, we identify multiple checkpoints in snRNA biogenesis monitored by quality control machineries that subject defective snRNAs to degradation and prevent their assembly into spliceosomes. We show that variant U1 snRNAs produced from human pseudogenes, some at rates approaching canonical snRNAs, are impaired in 3' cleavage and targeted for degradation by the NEXT-exosome while failures in subsequent protein assembly steps promote NEXT-exosome- or terminal uridylyl transferase 4/7-mediated degradation. These pathways also repress mutant snRNAs associated with human developmental disorders. Impeding snRNA quality control causes formation of aberrant spliceosomes and altered pre-mRNA splicing. These findings define checkpoints in snRNA biogenesis that safeguard pre-mRNA splicing and represent potential therapeutic targets for human disorders associated with snRNA mutations.
Keywords
RNA, Small Nuclear, Spliceosomes, Humans, RNA Splicing, Pseudogenes, RNA Precursors, RNA Stability, Mutation, Integrator, NEXT–exosome, RNA quality control, TUT4, TUT7, neurodevelopmental disorders (NDD), pseudogenes, snRNA, spliceosome, splicing
Published Open-Access
yes
Recommended Citation
Ma, Tiantai; Huntington, Claire; Song, Zhuoyi; et al., "Multiple Quality Control Checkpoints Safeguard Small Nuclear Rna Biogenesis and Prevent Assembly of Aberrant Spliceosomes" (2026). Faculty, Staff and Students Publications. 8682.
https://digitalcommons.library.tmc.edu/baylor_docs/8682