Researchers discover mechanism that protects tissue after faulty gene expression

2 minutes, 39 seconds Read



Genetic material, in the form of DNA, contains information that is crucial for the proper functioning of every human and animal cell. From this information store, the cell’s functional unit, DNA, and an RNA intermediate between proteins are produced. During this process, genetic information must be adapted for specific cell functions. Information that is not needed (introns) is cut out of the RNA and important elements for proteins (exons) are preserved. A team of researchers led by Prof. Dr. Mirka Uhlirova at the University of Cologne’s CECAD Cluster of Excellence in Aging Research has now discovered that if the processing of this information no longer works properly, a protein complex (C/EBP heterodimer) is activated and signals. cells toward a dormant state, known as cellular senescence. The findings are published under the title ‘Xrp1 governs the stress response program to spliceosome dysfunction’ Nucleic acid research.

All eukaryotes (i.e. organisms in which DNA is enclosed within the cell nucleus) have a spliceosome. It is a machine that joins exons for ‘splicing’, removing introns and forming messenger RNA (mRNA). Spliceosome defects lead to diseases known as spliceopathies, which can affect various tissues and manifest as retinal degeneration syndromes or myelodysplastic syndromes, a group of bone marrow diseases that affect the blood.

In the study, the Uhlirova lab used the model organism Drosophila melanogaster, a fruit fly, to investigate how cells in a developing organism respond to spliceosome defects. Scientists used a combination of genomics and functional genetics to determine the role of individual genes and the interactions between them. Studies have shown that cells with a defective spliceosomal U5 snRNP (U5 small nuclear ribonucleoprotein particle) activate a stress signaling response and cellular behavior characteristic of cellular senescence. The senescence program alters important cell functions. It prevents cells from dividing while stimulating their secretion. Senescence is triggered to preserve damaged cells, as their immediate elimination would cause more harm than good. However, senescent cell accumulation can have negative effects on a tissue as well as the whole organism. Therefore, these cells are eventually eliminated.

Uhlirova’s team identified the C/EBP-heterodimer protein complex, Xrp1/Irbp18, as an important driver of the stress response program caused by defective splicing. Upregulation of Xrp1/Irbp18 in damaged cells leads to increased protein production and induces a senescence-like state. “Sensitization is a double-edged sword,” says Uhlirova. An advantage of senescent cells is that they are not eliminated by cell death at the same time, thus maintaining tissue integrity. After all, partially intact tissue is better than anything. However, these cells cause problems in the long term, as their accumulation promotes disease and aging.

“A functional spliceosome is a fundamental prerequisite for healthy cells, tissues and whole organisms,” he concluded. “Further investigation of the stress signaling program we identified will be critical to further unpack the complex responses triggered by defects in the essential machinery that regulates gene expression—and how we can influence them.” In the future, the results may contribute to the development of therapeutic approaches to treat diseases caused by spliceosome defects.

Source:

Journal Reference:

Stankovic, D., etc (2024) Xrp1 directs the stress response program to spliceosome dysfunction.. Nucleic acid research. doi.org/10.1093/nar/gkae055.



Similar Posts

Leave a Reply

Your email address will not be published. Required fields are marked *