FUBP1 is a general splicing factor facilitating 3′ splice site recognition and splicing of long introns

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

doi:10.1016/j.molcel.2023.07.002

FUBP1 is a general splicing factor facilitating 3′ splice site recognition and splicing of long introns

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 EbersbergerStefan Legewie, Katja Luck, Michael Sattler, Julian König

Chair of Biomolecular NMR-Spectroscopy

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	2653-2672.e15
Journal	Molecular Cell
Volume	83
Issue number	15
DOIs	https://doi.org/10.1016/j.molcel.2023.07.002
State	Published - 3 Aug 2023

Keywords

NMR spectroscopy
cancer mutations
exon/intron definition
iCLIP
intrinsically disordered regions
intron bridging
multivalent interactions
protein-RNA interactions
splice site recognition
splicing

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.molcel.2023.07.002

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Ebersberger, S., Hipp, C., Mulorz, M. M., Buchbender, A., Hubrich, D., Kang, H. S., Martínez-Lumbreras, S., Kristofori, P., Sutandy, F. X. R., Llacsahuanga Allcca, L., Schönfeld, J., Bakisoglu, C., Busch, A., Hänel, H., Tretow, K., Welzel, M., Di Liddo, A., Möckel, M. M., Zarnack, K., ... König, J. (2023). FUBP1 is a general splicing factor facilitating 3′ splice site recognition and splicing of long introns. Molecular Cell, 83(15), 2653-2672.e15. https://doi.org/10.1016/j.molcel.2023.07.002

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title = "FUBP1 is a general splicing factor facilitating 3′ splice site recognition and splicing of long introns",

abstract = "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.",

keywords = "NMR spectroscopy, cancer mutations, exon/intron definition, iCLIP, intrinsically disordered regions, intron bridging, multivalent interactions, protein-RNA interactions, splice site recognition, splicing",

author = "Stefanie Ebersberger and Clara Hipp and Mulorz, \{Miriam M.\} and Andreas Buchbender and Dalmira Hubrich and Kang, \{Hyun Seo\} and Santiago Mart{\'i}nez-Lumbreras and Panajot Kristofori and Sutandy, \{F. X.Reymond\} and \{Llacsahuanga Allcca\}, Lidia and Jonas Sch{\"o}nfeld and Cem Bakisoglu and Anke Busch and Heike H{\"a}nel and Kerstin Tretow and Mareen Welzel and \{Di Liddo\}, Antonella and M{\"o}ckel, \{Martin M.\} and Kathi Zarnack and Ingo Ebersberger and Stefan Legewie and Katja Luck and Michael Sattler and Julian K{\"o}nig",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = aug,

day = "3",

doi = "10.1016/j.molcel.2023.07.002",

language = "English",

volume = "83",

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journal = "Molecular Cell",

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Ebersberger, S, Hipp, C, Mulorz, MM, Buchbender, A, Hubrich, D, Kang, HS, Martínez-Lumbreras, S, Kristofori, P, Sutandy, FXR, Llacsahuanga Allcca, L, Schönfeld, J, Bakisoglu, C, Busch, A, Hänel, H, Tretow, K, Welzel, M, Di Liddo, A, Möckel, MM, Zarnack, K, Ebersberger, I, Legewie, S, Luck, K, Sattler, M & König, J 2023, 'FUBP1 is a general splicing factor facilitating 3′ splice site recognition and splicing of long introns', Molecular Cell, vol. 83, no. 15, pp. 2653-2672.e15. https://doi.org/10.1016/j.molcel.2023.07.002

TY - JOUR

T1 - FUBP1 is a general splicing factor facilitating 3′ splice site recognition and splicing of long introns

AU - Ebersberger, Stefanie

AU - Hipp, Clara

AU - Mulorz, Miriam M.

AU - Buchbender, Andreas

AU - Hubrich, Dalmira

AU - Kang, Hyun Seo

AU - Martínez-Lumbreras, Santiago

AU - Kristofori, Panajot

AU - Sutandy, F. X.Reymond

AU - Llacsahuanga Allcca, Lidia

AU - Schönfeld, Jonas

AU - Bakisoglu, Cem

AU - Busch, Anke

AU - Hänel, Heike

AU - Tretow, Kerstin

AU - Welzel, Mareen

AU - Di Liddo, Antonella

AU - Möckel, Martin M.

AU - Zarnack, Kathi

AU - Ebersberger, Ingo

AU - Legewie, Stefan

AU - Luck, Katja

AU - Sattler, Michael

AU - König, Julian

PY - 2023/8/3

Y1 - 2023/8/3

N2 - 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.

AB - 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.

KW - NMR spectroscopy

KW - cancer mutations

KW - exon/intron definition

KW - iCLIP

KW - intrinsically disordered regions

KW - intron bridging

KW - multivalent interactions

KW - protein-RNA interactions

KW - splice site recognition

KW - splicing

UR - http://www.scopus.com/inward/record.url?scp=85166539523&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2023.07.002

DO - 10.1016/j.molcel.2023.07.002

M3 - Article

C2 - 37506698

AN - SCOPUS:85166539523

SN - 1097-2765

VL - 83

SP - 2653-2672.e15

JO - Molecular Cell

JF - Molecular Cell

IS - 15

ER -

FUBP1 is a general splicing factor facilitating 3′ splice site recognition and splicing of long introns

Abstract

Keywords

UN SDGs

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