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FUBP1 is a general splicing factor facilitating 3' splice site recognition and splicing of long introns.
Mol. Cell 83, 2653-2672.e15 (2023)
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
ISSN (print) / ISBN
1097-2765
e-ISSN
1097-4164
Journal
Molecular Cell
Quellenangaben
Volume: 83,
Issue: 15,
Pages: 2653-2672.e15
Publisher
Elsevier
Publishing Place
50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Structural Biology (STB)
Grants
Marie Curie Actions (MSCA)
EU
Fonds der Chemischen Industrie
DFG
Deutsche Forschungsgemeinschaft
EU
Fonds der Chemischen Industrie
DFG
Deutsche Forschungsgemeinschaft