High-Resolution Images Reveal How Cells Discard Faulty Spliceosomes

The spliceosome, a highly sophisticated molecular machine, plays a crucial role in ensuring that genetic information is accurately assembled into mature mRNA after being transcribed from DNA. This splicing process is essential for producing functional proteins that drive critical biological functions.

When the spliceosome malfunctions, it can lead to severe diseases. Now, for the first time, researchers at Heidelberg University’s Biochemistry Center (BZH), in collaboration with colleagues from the Australian National University, have captured a high-resolution image of a defective, “blocked” spliceosome. Their work also sheds light on how the cell identifies and eliminates these faulty complexes.

Genetic information in all living organisms is encoded in DNA, with most genes in higher organisms arranged in a mosaic-like structure. To translate these instructions into proteins, the genetic sequences are first transcribed into precursor messenger RNA (pre-mRNA). The spliceosome then processes these precursors by removing non-coding regions (introns) and linking coding regions (exons) to form a continuous, functional mRNA strand.

Errors in splicing are a major contributor to inherited genetic disorders and are associated with neurodevelopmental diseases and cancer. While it was known that the spliceosome has built-in quality control mechanisms, the details of how it detects and disposes of errors remain unclear.

Led by BZH director Professor Dr. Irmgard Sinning, the research team used the fission yeast Schizosaccharomyces pombe, a widely studied model organism in cell biology, to investigate spliceosome quality control. By isolating defective spliceosomes, they employed cryo-electron microscopy and molecular markers to analyze their structure in unprecedented detail.

“The largely stable structure of the spliceosome center allowed us to obtain high-resolution insights. For the first time, we could visualize a discarded spliceosome at the atomic level. However, analyzing the flexible peripheral components posed a significant challenge.”
— Dr. Komal Soni, Structural Biologist, Heidelberg University Biochemistry Center

Using this structural data, the team identified the types of errors that arise during splicing, the mechanisms the spliceosome uses to recognize faulty processes, and how the defective complexes are dismantled. Their findings also revealed that the proteins responsible for this quality control are conserved across eukaryotic organisms, from yeast to humans—suggesting that these mechanisms have remained largely unchanged through evolution.

This study was part of a long-term collaboration between Professor Sinning’s team and Professor Dr. Tamas Fischer, an expert in RNA surveillance at the Australian National University. Additional contributions came from Professor Dr. Henning Urlaub’s research group at the Max Planck Institute for Multidisciplinary Sciences in Göttingen.

The findings, supported by the German Research Foundation and the Australian Research Council, were published in Nature Structural & Molecular Biology.