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Peer-reviewedCC BY 4.0Nature

Mechanism of spliceosome termination

  • Vytaute Boreikaite1
  • Rupert Faraway1,2,3
  • Matthias K. Vorländer1
  • Alexander W. Phillips1
  • Leonie Opitz1
  • Moritz Wanke2,3
  • George Yakoub4
  • Gerald Raffl2,3,5
  • Laura Fin1
  • Román González-Prieto6,7
  • Martijn S. Luijsterburg4
  • Stefan L. Ameres2,3
1 more authors
  • Clemens Plaschka1
7 affiliations
  1. 1Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria
  2. 2Max Perutz Labs, Vienna BioCenter (VBC), Vienna, Austria
  3. 3University of Vienna, Max Perutz Labs, Vienna, Austria
  4. 4Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
  5. 5Vienna BioCenter PhD Program, Doctoral School of the University of Vienna and Medical University of Vienna, Vienna, Austria
  6. 6Andalusian Centre for Regenerative Medicine and Molecular Biology (CABIMER), Universidad de Sevilla-CSIC–Universidad Pablo de Olavide-Junta de Andalucía, Sevilla, Spain
  7. 7Departament of Cell Biology, Faculty of Biology, University of Sevilla, Sevilla, Spain
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Abstract

After excising an intron from pre-mRNA, the spliceosome remains trapped in a non-productive complex bound to the intron1–5. Termination of this complex is critical for spliceosome recycling and intron decay6, but the mechanism remains unknown. Here we present cryo-electron microscopy structures of human spliceosomes at two sequential stages of termination. First, the RNA helicases DHX15 and Aquarius unwind the RNA active site of the spliceosome, releasing bound components including U2 snRNA and extracting the buried intron–lariat branch point. The branch point is then debranched by the spliceosome-tethered enzyme DBR1, generating the previously unknown debranched intron spliceosome. This state recruits the RNA helicase DHX35 with its co-factors GPATCH1–WDR83, assisted by YJU2B. DHX35 ejects the debranched intron from the U6 snRNA–5′ splice site duplex, driving spliceosome disassembly and intron turnover. In defective spliceosomes stalled on aberrant introns, YJU2B partners with LENG1 to guide DHX35–GPATCH1–WDR83 for termination through spliceosome quality control. Together, we reveal the mechanism of regular spliceosome termination and its parallels with spliceosome quality control, ensuring accurate and efficient pre-mRNA splicing.

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Cite

BibTeXRIS
BibTeX
@article{boreikaite2026mechanism,
  title = {{Mechanism of spliceosome termination}},
  author = {Vytaute Boreikaite and Rupert Faraway and Matthias K. Vorländer and Alexander W. Phillips and Leonie Opitz and Moritz Wanke and George Yakoub and Gerald Raffl and Laura Fin and Román González-Prieto and Martijn S. Luijsterburg and Stefan L. Ameres and Clemens Plaschka},
  journal = {Nature},
  year = {2026},
  month = oct,
  doi = {10.1038/s41586-026-11101-6},
  url = {https://doi.org/10.1038/s41586-026-11101-6},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Mechanism of spliceosome termination
AU  - Vytaute Boreikaite
AU  - Rupert Faraway
AU  - Matthias K. Vorländer
AU  - Alexander W. Phillips
AU  - Leonie Opitz
AU  - Moritz Wanke
AU  - George Yakoub
AU  - Gerald Raffl
AU  - Laura Fin
AU  - Román González-Prieto
AU  - Martijn S. Luijsterburg
AU  - Stefan L. Ameres
AU  - Clemens Plaschka
PY  - 2026
DA  - 2026/10/07
JO  - Nature
DO  - 10.1038/s41586-026-11101-6
UR  - https://doi.org/10.1038/s41586-026-11101-6
AB  - After excising an intron from pre-mRNA, the spliceosome remains trapped in a non-productive complex bound to the intron1–5. Termination of this complex is critical for spliceosome recycling and intron decay6, but the mechanism remains unknown. Here we present cryo-electron microscopy structures of human spliceosomes at two sequential stages of termination. First, the RNA helicases DHX15 and Aquarius unwind the RNA active site of the spliceosome, releasing bound components including U2 snRNA and extracting the buried intron–lariat branch point. The branch point is then debranched by the spliceosome-tethered enzyme DBR1, generating the previously unknown debranched intron spliceosome. This state recruits the RNA helicase DHX35 with its co-factors GPATCH1–WDR83, assisted by YJU2B. DHX35 ejects the debranched intron from the U6 snRNA–5′ splice site duplex, driving spliceosome disassembly and intron turnover. In defective spliceosomes stalled on aberrant introns, YJU2B partners with LENG1 to guide DHX35–GPATCH1–WDR83 for termination through spliceosome quality control. Together, we reveal the mechanism of regular spliceosome termination and its parallels with spliceosome quality control, ensuring accurate and efficient pre-mRNA splicing.
SN  - 0028-0836
SN  - 1476-4687
ER  -