Mechanism for the initiation of spliceosome disassembly

Matthias K. Vorländer, Patricia Rothe, Justus Kleifeld, Eric D. Cormack, Lalitha Veleti, Daria Riabov-Bassat, Laura Fin, Alex W. Phillips, Luisa Cochella () and Clemens Plaschka ()
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Matthias K. Vorländer: Vienna BioCenter (VBC)
Patricia Rothe: Vienna BioCenter (VBC)
Justus Kleifeld: Vienna BioCenter (VBC)
Eric D. Cormack: Johns Hopkins University School of Medicine
Lalitha Veleti: Vienna BioCenter (VBC)
Daria Riabov-Bassat: Vienna BioCenter (VBC)
Laura Fin: Vienna BioCenter (VBC)
Alex W. Phillips: Vienna BioCenter (VBC)
Luisa Cochella: Vienna BioCenter (VBC)
Clemens Plaschka: Vienna BioCenter (VBC)

Nature, 2024, vol. 632, issue 8024, 443-450

Abstract: Abstract Precursor-mRNA (pre-mRNA) splicing requires the assembly, remodelling and disassembly of the multi-megadalton ribonucleoprotein complex called the spliceosome1. Recent studies have shed light on spliceosome assembly and remodelling for catalysis2–6, but the mechanism of disassembly remains unclear. Here we report cryo-electron microscopy structures of nematode and human terminal intron lariat spliceosomes along with biochemical and genetic data. Our results uncover how four disassembly factors and the conserved RNA helicase DHX15 initiate spliceosome disassembly. The disassembly factors probe large inner and outer spliceosome surfaces to detect the release of ligated mRNA. Two of these factors, TFIP11 and C19L1, and three general spliceosome subunits, SYF1, SYF2 and SDE2, then dock and activate DHX15 on the catalytic U6 snRNA to initiate disassembly. U6 therefore controls both the start5 and end of pre-mRNA splicing. Taken together, our results explain the molecular basis of the initiation of canonical spliceosome disassembly and provide a framework to understand general spliceosomal RNA helicase control and the discard of aberrant spliceosomes.

Date: 2024
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DOI: 10.1038/s41586-024-07741-1

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