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Structures of aberrant spliceosome intermediates on their way to disassembly

Intron removal during pre-mRNA splicing is of extraordinary complexity and its disruption causes a vast number of genetic diseases in humans. While key steps of the canonical spliceosome cycle have been revealed by combined structure-function analyses, structural information on an aberrant spliceoso...

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Main Authors: Soni, Komal (Author) , Horvath, Attila (Author) , Dybkov, Olexandr (Author) , Schwan, Merlin (Author) , Trakansuebkul, Sasanan (Author) , Flemming, Dirk (Author) , Wild, Klemens (Author) , Urlaub, Henning (Author) , Fischer, Tamás (Author) , Sinning, Irmgard (Author)
Format: Article (Journal)
Language:English
Published: 20 January 2025
In: Nature structural & molecular biology
Year: 2025, Volume: 32, Issue: 5, Pages: 914-925
ISSN:1545-9985
DOI:10.1038/s41594-024-01480-7
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41594-024-01480-7
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41594-024-01480-7
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Author Notes:Komal Soni, Attila Horvath, Olexandr Dybkov, Merlin Schwan, Sasanan Trakansuebkul, Dirk Flemming, Klemens Wild, Henning Urlaub, Tamás Fischer, Irmgard Sinning
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Summary:Intron removal during pre-mRNA splicing is of extraordinary complexity and its disruption causes a vast number of genetic diseases in humans. While key steps of the canonical spliceosome cycle have been revealed by combined structure-function analyses, structural information on an aberrant spliceosome committed to premature disassembly is not available. Here, we report two cryo-electron microscopy structures of post-Bact spliceosome intermediates from Schizosaccharomyces pombe primed for disassembly. We identify the DEAH-box helicase-G-patch protein pair (Gih35-Gpl1, homologous to human DHX35-GPATCH1) and show how it maintains catalytic dormancy. In both structures, Gpl1 recognizes a remodeled active site introduced by an overstabilization of the U5 loop I interaction with the 5′ exon leading to a single-nucleotide insertion at the 5′ splice site. Remodeling is communicated to the spliceosome surface and the Ntr1 complex that mediates disassembly is recruited. Our data pave the way for a targeted analysis of splicing quality control.
Item Description:Online veröffentlicht: 20 Januar 2025
Gesehen am 06.08.2025
Physical Description:Online Resource
ISSN:1545-9985
DOI:10.1038/s41594-024-01480-7

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