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Splicing of pre-mRNAs critically contributes to gene regulation and proteome expansion in eukaryotes, but our understanding of the recognition and pairing of splice sites during spliceosome assembly lacks detail. Here, we identify the multidomain RNA-binding protein FUBP1 as a key splicing factor that binds to a hitherto unknown cis-regulatory motif. By collecting NMR, structural, and in vivo interaction data, we demonstrate that FUBP1 stabilizes U2AF2 and SF1, key components at the 3' splice site, through multivalent binding interfaces located within its disordered regions. Transcriptional profiling and kinetic modeling reveal that FUBP1 is required for efficient splicing of long introns, which is impaired in cancer patients harboring FUBP1 mutations. Notably, FUBP1 interacts with numerous U1 snRNP-associated proteins, suggesting a unique role for FUBP1 in splice site bridging for long introns. We propose a compelling model for 3' splice site recognition of long introns, which represent 80% of all human introns. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.


Stefanie Ebersberger, Clara Hipp, Miriam M Mulorz, Andreas Buchbender, Dalmira Hubrich, Hyun-Seo Kang, Santiago Martínez-Lumbreras, Panajot Kristofori, F X Reymond Sutandy, Lidia Llacsahuanga Allcca, Jonas Schönfeld, Cem Bakisoglu, Anke Busch, Heike Hänel, Kerstin Tretow, Mareen Welzel, Antonella Di Liddo, Martin M Möckel, Kathi Zarnack, Ingo Ebersberger, Stefan Legewie, Katja Luck, Michael Sattler, Julian König. FUBP1 is a general splicing factor facilitating 3' splice site recognition and splicing of long introns. Molecular cell. 2023 Aug 03;83(15):2653-2672.e15

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PMID: 37506698

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