Team discovers mechanism that protects tissues after faulty gene expression

A study from the CECAD excellence group in aging research at the University of Cologne has identified a protein complex activated by defects in the spliceosome, the molecular scissors that process genetic information. Future research could lead to new therapeutic approaches to treat diseases caused by defective splicing.

Genetic material, in the form of DNA, contains information crucial for the proper functioning of each human and animal cell. From this repository of information, RNA, the intermediate between DNA and protein, the functional unit of the cell, is generated. During this process, genetic information must be tailored to specific cellular functions. Unnecessary information (introns) is removed from the RNA and important protein components (exons) are preserved.

A team of researchers led by Professor Dr. Mirka Uhlirova from the CECAD Excellence Group in Aging Research at the University of Cologne discovered that if the processing of this information no longer functions properly, a protein complex (C/EBP heterodimer ) is activated and directs the cell towards a state of dormancy, called cellular senescence. The results appear under the title “Xrp1 governs the stress response program in spliceosome dysfunction” in Nucleic acid research.

All eukaryotes (i.e. organisms in which DNA is enclosed in the cell nucleus) have a spliceosome. It is a machine that performs “splicing,” removing introns and joining exons to form messenger RNA (mRNA). Spliceosome dysfunction leads to diseases called spliceosomopathies, which can affect many different tissues and manifest as retinal degeneration or myelodysplastic syndrome, a group of bone marrow diseases affecting the blood.

In the study, the Uhlirova lab used the model organism Drosophila melanogaster, a fruit fly, to study how cells in a developing organism respond to spliceosome dysfunction. Scientists used a combination of genomics and functional genetics to determine the role of individual genes and their interactions.

The study showed that cells suffering from a defective spliceosomal U5 snRNP (small U5 nuclear ribonucleoprotein particle) activate a stress signaling response and cellular behaviors characteristic of cellular senescence. The senescence program modifies crucial cell functions. It prevents cells from dividing while stimulating their secretion. Senescence is triggered to preserve damaged cells, as their immediate removal would cause more harm than good. However, the accumulation of senescent cells can have a negative impact on a tissue as well as the entire organism. These cells are therefore finally eliminated.

Uhlirova’s team identified the C/EBP-heterodimer protein complex, Xrp1/Irbp18, as the essential driver of the stress response program caused by defective splicing. Upregulation of Xrp1/Irbp18 in damaged cells led to increased protein production and induced a senescence-like state.

“Senescence is a double-edged sword,” Uhlirova said. An advantage of senescent cells is that they are not all eliminated at once by cell death, thus preserving the integrity of the tissue. After all, it’s better to have partially intact tissue than none at all. However, these cells create long-term problems because their accumulation promotes disease and aging.

“A functional spliceosome is a fundamental prerequisite for healthy cells, tissues and the entire organism,” she concluded. “Further investigation into the stress signaling program we identified will be important to better understand the complex responses triggered by defects in essential machinery controlling gene expression and how we can influence them.”

In the future, the results could contribute to the development of therapeutic approaches to treat diseases caused by spliceosome dysfunctions.