Every time a cell reads a gene, it must cut out the non-coding junk and stitch the useful bits back together—and a five-protein machine called the intron-binding complex (IBC) is the tool that makes the cut happen. This matters because the splicing process is one of the most fundamental steps in turning genetic instructions into working proteins. Errors in splicing cause dozens of human diseases, including spinal muscular atrophy and some cancers. Yet the IBC’s exact role has remained a black box: how does it physically rearrange the spliceosome to trigger the chemical cut, and how does it also handle a second task—processing small RNA sequences called SNORDs that are essential for building ribosomes? Without knowing the IBC’s structure and mechanics, researchers cannot understand what goes wrong when splicing fails. This project is fundamental science. It will use cryo-electron microscopy to capture snapshots of the spliceosome stalled at precise stages, revealing the IBC’s 3D shape and its moving parts. Success would give biologists a molecular blueprint of a core cellular machine. Past work on similar fundamental splicing mechanisms led directly to antisense therapies for spinal muscular atrophy—a reminder that understanding how cells edit their RNA can, over time, open routes to treatments for conditions rooted in splicing errors.
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RNA splicing is a crucial phase in processing the genetic information. This process is carried out by complex particles known as spliceosomes, considered some of the most sophisticated cellular machines. During splicing, spliceosomes remove non-coding regions (introns) from RNA transcripts and then reconnect the coding regions (exons). This drastic "editing" ensures that the genetic information is accurately translated into proteins. Beyond catalyzing RNA splicing, spliceosomes can process specific sequences of intronic RNAs known as SNORD (small nucleolar RNA C/D box). These RNAs are vital in forming small nucleolar ribonucleoproteins (snoRNPs), which later play essential roles in the maturation of ribosomes. Spliceosomes can actively shape the SNORDs and induce their association with specific proteins to construct functional snoRNPs. For both RNA splicing and SNORD processing, spliceosomes employ a group of five proteins that form the intron-binding complex (IBC). Central to the IBC's functionality is one of its components - the RNA helicase Aquarius, which acts as a pivotal molecular motor. Our objectives are to deeply understand two areas: first, how the IBC promotes the restructuring of spliceosomes to initiate the splicing chemistry. Second, we aim to explore how the IBC coordinates the processing of SNORD sequences and splicing within spliceosomes. As the spliceosomes are very dynamic molecular machines, permanently modifying their composition and conformation, a key challenge is to find means of stalling them at precise stages, and then to resolve their 3D structure with cryogenic electron microscopy (cryo-EM). We will use advanced methodologies of cell cultivation in a bioreactor, proteomic mass-spectrometry, protein and RNA biochemistry, and cryo-EM. This integrative approach will enable us to reconstruct intermediate stages of spliceosomes, to dissect and visualize RNA splicing and SNORD processing at a molecular level. Positioned at the forefront of RNA biology and cryo-EM structural biology, this research aligns with the BBSRC's objective to maintain the UK's leadership in the "bio-revolution". It aims to enhance our fundamental understanding of biological systems through innovative ideas and impactful research, crucial for biotechnological advancements and an integrated understanding of health. Additionally, this project will contribute to nurturing and developing talented scientists, promoting a flourishing, innovative, and inclusive research culture.
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