Unlocking Cellular Secrets: Team Discovers Protein Complex Activated by Faulty Gene Expression

A groundbreaking study at the University of Cologne’s CECAD Cluster of Excellence in Aging Research has revealed a novel mechanism that protects tissues when faced with faulty gene expression. The research, led by Professor Dr. Mirka Uhlirova, identified a protein complex, Xrp1-Irbp18, activated by defects in the spliceosome—the molecular scissors responsible for processing genetic information.

The spliceosome’s role in the accurate processing of genetic information is crucial for cellular function. When this process goes awry, the newly discovered protein complex activates a cellular dormancy state known as senescence, a response aimed at preserving damaged cells.

Using the fruit fly Drosophila melanogaster as a model organism, the research team delved into how cells respond to spliceosome malfunction. The study, published in Nucleic Acids Research, uncovered that cells with defective spliceosomal U5 small nuclear ribonucleoprotein particles (snRNPs) trigger a stress response and exhibit behaviors characteristic of cellular senescence.

The senescence program, activated to protect damaged cells, prevents them from dividing while stimulating protein secretion. While senescent cells play a role in maintaining tissue integrity, their accumulation over time can lead to disease and aging.

The Xrp1-Irbp18 protein complex emerged as a critical driver of the stress response program caused by faulty splicing. Upregulation of Xrp1/Irbp18 in damaged cells led to increased protein production and induced a senescence-like state.

Professor Uhlirova emphasized the double-edged nature of senescence, noting its advantages in preserving tissue integrity but acknowledging the long-term issues associated with the accumulation of senescent cells.

“A functioning spliceosome is a basic prerequisite for healthy cells, tissue, and the entire organism,” said Professor Uhlirova. The study’s findings could pave the way for therapeutic approaches to address diseases caused by spliceosome malfunctions, offering new insights into the complex responses triggered by defects in gene expression control machinery.

More information: Dimitrije Stanković et al, Xrp1 governs the stress response program to spliceosome dysfunction, Nucleic Acids Research (2024). DOI: 10.1093/nar/gkae055