Identification of a key factor for splicing long introns

Mutations in FUBP1 cause defective gene regulation in glioma cells

Pre-mRNA splicing is an essential step in the maturation of mRNA in which introns are removed and the remaining exons are linked to create a mature mRNA as template for proteins. This is a vital aspect of eukaryotic gene regulation and provides proteome diversity by alternative splicing, allowing the expression of different protein variants (isoforms) from a single gene. It is a heavily regulated mechanism controlled by hundreds of factors whose activity depends on environmental, cellular and developmental conditions. Its misregulation is often linked to genetic diseases as well as cancer and cancer progression.

In collaboration with the research group of Julian König (Institute of Molecular Biology, Mainz, Germany), Prof. Sattler´s lab (Institute of Structural Biology, STB) has discovered that the multidomain RNA-binding protein FUBP1 (Far Upstream element Binding Protein 1) plays a key role in the splicing of long introns. By combining NMR spectroscopy, molecular biology techniques, and computational modelling, the researchers found that FUBP1 binds to a cis-regulatory motif in the pre-mRNA and stabilizes the binding of key components at the 3’ splice site (U2AF2, SF1), facilitating the recognition of the correct intron-exon boundary. Additionally, multivalent interactions of FUBP1 with several U1 snRNP-associated proteins suggest a role of FUBP1 in bridging 5’ and 3’ splice sites. Transcriptional profiling revealed that FUBP1 is required for the splicing of long introns, which represent 80 % of all human introns. Indeed, sequencing data from glioma patients showed that cancer patients harbouring FUBP1 loss-of-function mutations have impaired splicing of long introns compared to patients with mutations in other splicing factors.

The results of the study were published in Molecular Cell.

DOI: https://doi.org/10.1016/j.molcel.2023.07.002

This study was supported by SPP1935, Fonds der Chemischen Industrie for Kekulé fellowship, H2020 Marie Curie Fellowship  and IMB Genomics Core Facility