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PreprintCC BY 4.0Genes & Development

Multiple quality control checkpoints safeguard small nuclear RNA biogenesis and prevent assembly of aberrant spliceosomes

  • Tiantai Ma1
  • Claire Huntington1
  • Zhuoyi Song2
  • Rea M. Lardelli1
  • Eric L. Van Nostrand2
  • Jens Lykke-Andersen1
  1. 1Department of Molecular Biology, School of Biological Sciences, University of California San Diego, La Jolla, California 92093, USA
  2. 2Therapeutic Innovation Center and the Verna Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas 77030, USA
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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.

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Cite

BibTeXRIS
BibTeX
@misc{ma2026multiple,
  title = {{Multiple quality control checkpoints safeguard small nuclear RNA biogenesis and prevent assembly of aberrant spliceosomes}},
  author = {Tiantai Ma and Claire Huntington and Zhuoyi Song and Rea M. Lardelli and Eric L. Van Nostrand and Jens Lykke-Andersen},
  howpublished = {Genes \& Development},
  year = {2026},
  month = nov,
  doi = {10.1101/gad.353690.126},
  url = {https://doi.org/10.1101/gad.353690.126},
  note = {CC BY 4.0},
}
RIS
TY  - UNPB
TI  - Multiple quality control checkpoints safeguard small nuclear RNA biogenesis and prevent assembly of aberrant spliceosomes
AU  - Tiantai Ma
AU  - Claire Huntington
AU  - Zhuoyi Song
AU  - Rea M. Lardelli
AU  - Eric L. Van Nostrand
AU  - Jens Lykke-Andersen
PY  - 2026
DA  - 2026/11/01
PB  - Genes & Development
DO  - 10.1101/gad.353690.126
UR  - https://doi.org/10.1101/gad.353690.126
AB  - 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.
SN  - 0890-9369
SN  - 1549-5477
ER  -