IMB researchers identify a key splicing factor for splicing long introns

RESEARCH HIGHLIGHTS

The research groups of Julian König and Katja Luck (Institute of Molecular Biology, IMB, Mainz, Germany), together with the group of Michael Sattler (Institute of Structural Biology and Technical University of Munich, Germany) have discovered that the proto-oncogene FUBP1 has a previously unknown function as a core splicing component at long introns. They find that FUBP1 is responsible for stabilising the binding of other splicing factors to the 3’ splice site. Additionally, FUBP1 helps promote pairing of splice sites across introns, thereby encouraging spliceosome formation. These findings can help researchers better understand the complex and dynamic splicing processes. Furthermore, it can lead to the design of new and improved anticancer treatments to target disrupted splicing in cancer cells.

Splicing is an essential step of mRNA maturation in eukaryotes, during which the non-coding introns are cut out of the pre-mRNA and the coding exons are joined together, creating a mature mRNA. This process is often disrupted in cancer cells, resulting in exon skipping and/or intron inclusion. Studies show that up to 30% of cancers have more alternative splicing than normal cells. Such disruption of splicing can promote cancer growth by upregulating genes that increase cell survival, growth and resistance to anticancer treatments, as well as downregulating genes that promote apoptosis.

A common cause of these splicing disruptions is loss-of-function mutations in the proteins that catalyse splicing. Splicing is a complex, multistep process involving hundreds of proteins: some are responsible for recognising the splice sites, while others stabilise the binding of the spliceosome to the mRNA or cut out the introns and join the exons. However, our understanding of the proteins and interactions involved is still incomplete. To better understand how mRNAs are spliced in normal cells and how this is disrupted in cancer, Julian and his colleagues Katja and Michael set out to study FUBP1 (far upstream binding protein 1), which is known to be frequently mutated in gliomas, and to determine whether it has a role in splicing.

Through careful molecular and computational analysis, the researchers discovered that FUBP1 has two key roles in regulating the splicing of long introns. First, FUBP1 stabilises the binding of other splicing proteins to the 3’ splice site, helping the cell to recognise the correct exon-intron boundary. Second, FUBP1 helps promote the pairing of splice sites on either side of long introns, bridging them to facilitate the subsequent catalytic steps of cutting out the introns and joining exons. Indeed, when the researchers analysed sequencing data from glioma patients, they found that patients with FUBP1 loss-of-function mutations had more skipping of exons with long adjacent introns than patients with mutations in other splicing factors.

Julian says, “Long introns comprise over 80% of the introns in the human genome, but they are particularly difficult to splice and require more complex regulation. Our findings now reveal that FUBP1 plays a key role in this regulation. By gaining a better understanding of the proteins that regulate splicing, we can contribute to the design of new anticancer drugs that target the splicing machinery, creating new therapies to help people live longer and stay healthy in old age.”

The results of their study were published in the journal Molecular Cell.

^{Further details}

^{Further information can be found at https://doi.org/10.1016/j.molcel.2023.07.002}

^{Julian is a Group Leader at the Institute of Molecular Biology (IMB) Mainz. Further information about research in the König lab can be found at www.imb.de/koenig.}

^{Katja Luck is a Group Leader at the Institute of Molecular Biology (IMB) Mainz. Further information about research in the Luck lab can be found at www.imb.de/luck.}

^{About the Institute of Molecular Biology gGmbH}

^{The Institute of Molecular Biology gGmbH (IMB) is a centre of excellence in the life sciences that was established in 2011 on the campus of Johannes Gutenberg University Mainz (JGU). Research at IMB focuses on the cutting-edge fields of epigenetics, genome stability, ageing and RNA biology. The institute is a prime example of successful collaboration between a private foundation and government: The Boehringer Ingelheim Foundation has committed 154 million euros to be disbursed from 2009 until 2027 to cover the operating costs of research at IMB. The State of Rhineland-Palatinate has provided approximately 50 million euros for the construction of a state-of-the-art building and is giving a further 52 million in core funding from 2020 until 2027. For more information about IMB, please visit: www.imb.de.}

^{Boehringer Ingelheim Foundation}

^{The Boehringer Ingelheim Foundation is an independent, non-profit organization that is committed to the promotion of the medical, biological, chemical, and pharmaceutical sciences. It was established in 1977 by Hubertus Liebrecht (1931–1991), a member of the shareholder family of the Boehringer Ingelheim company. Through its funding programmes Plus 3, Exploration Grants and Rise up!, the Foundation supports excellent scientists during critical stages of their careers. It also endows the international Heinrich Wieland Prize, as well as awards for up-and-coming scientists in Germany. In addition, the Foundation funds institutional projects in Germany, such as the Institute of Molecular Biology (IMB) and the European Molecular Biology Laboratory (EMBL) in Heidelberg. www.boehringer-ingelheim-stiftung.de/en}

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