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Ebersberger, S.* ; Hipp, C. ; Mulorz, M.M.* ; Buchbender, A.* ; Hubrich, D.* ; Kang, H.-S. ; Martinez 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.* ; Ebersberger, I.* ; Legewie, S.* ; Luck, K.* ; Sattler, M. ; König, J.*

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

Mol. Cell 83, 2653-2672.e15 (2023)
Publ. Version/Full Text DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Nmr Spectroscopy ; Cancer Mutations ; Exon/intron Definition ; Iclip ; Intrinsically Disordered Regions ; Intron Bridging ; Multivalent Interactions ; Protein-rna Interactions ; Splice Site Recognition ; Splicing; Pre-messenger-rna; Far Upstream Element; Structural Basis; C-myc; Secondary Structure; Protein Structures; Exon Definition; U2 Snrnp; Regulatory Networks; Sh3 Domains
Language english
Publication Year 2023
HGF-reported in Year 2023
ISSN (print) / ISBN 1097-2765
e-ISSN 1097-4164
Journal Molecular Cell
Quellenangaben Volume: 83, Issue: 15, Pages: 2653-2672.e15 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-503000-001
Grants Marie Curie Actions (MSCA)
EU
Fonds der Chemischen Industrie
DFG
Deutsche Forschungsgemeinschaft
DOI 10.1016/j.molcel.2023.07.002
WOS ID 001053025300001
Scopus ID 85166539523
PubMed ID 37506698
Erfassungsdatum 2023-10-06
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