Understanding the dynamic design of the spliceosome

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) Vol. 49; no. 7; pp. 583 - 595
• Main Authors: Beusch, Irene, Madhani, Hiten D.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2024
• Subjects: adenosinetriphosphatase; Animals; ATPases; fidelity; Humans; Introns; pre-mRNA splicing; quality control; ribonucleoproteins; RNA; RNA Precursors - genetics; RNA Precursors - metabolism; RNA Splicing; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; snRNA; spliceosome; spliceosomes; Spliceosomes - metabolism; fidelity; spliceosome; ATPases; snRNA; pre-mRNA splicing
• DOI: 10.1016/j.tibs.2024.03.012
• ISSN: 0968-0004

The spliceosome is a highly dynamic and complex ATP-dependent ribonucleoprotein machine required for the splicing of mRNA precursors.Recent work demonstrates that in Saccharomyces cerevisiae, spliceosome fidelity is promoted by the Prp16 and Prp22 DEAH box ATPases, which function as molecular timers that, upon ATP hydrolysis, remove step-specific protein activators of catalysis.Additionally, research is showing that in human cells, quality control during the early phases of spliceosome assembly occurs via the G-patch protein SUGP1, which recruits the human ortholog of Prp43, hPrp43/DHX15, to early assembly complexes.Genetic analysis has revealed that specific factors prevent substrates from being erroneously repositioned during the many dynamic transitions that occur during spliceosome assembly and catalysis. The requirement for such factors may help explain the spliceosomes’ compositional complexity. The spliceosome catalyzes the splicing of pre-mRNAs. Although the spliceosome evolved from a prokaryotic self-splicing intron and an associated protein, it is a vastly more complex and dynamic ribonucleoprotein (RNP) whose function requires at least eight ATPases and multiple RNA rearrangements. These features afford stepwise opportunities for multiple inspections of the intron substrate, coupled with spliceosome disassembly for substrates that fail inspection. Early work using splicing-defective pre-mRNAs or small nuclear (sn)RNAs in Saccharomyces cerevisiae demonstrated that such checks could occur in catalytically active spliceosomes. We review recent results on pre-mRNA splicing in various systems, including humans, suggesting that earlier steps in spliceosome assembly are also subject to such quality control. The inspection–rejection framework helps explain the dynamic nature of the spliceosome. The spliceosome catalyzes the splicing of pre-mRNAs. Although the spliceosome evolved from a prokaryotic self-splicing intron and an associated protein, it is a vastly more complex and dynamic ribonucleoprotein (RNP) whose function requires at least eight ATPases and multiple RNA rearrangements. These features afford stepwise opportunities for multiple inspections of the intron substrate, coupled with spliceosome disassembly for substrates that fail inspection. Early work using splicing-defective pre-mRNAs or small nuclear (sn)RNAs in Saccharomyces cerevisiae demonstrated that such checks could occur in catalytically active spliceosomes. We review recent results on pre-mRNA splicing in various systems, including humans, suggesting that earlier steps in spliceosome assembly are also subject to such quality control. The inspection–rejection framework helps explain the dynamic nature of the spliceosome.