Genetic material in the form of DNA contains the information crucial for the proper functioning of every human and animal cell. RNA is generated from this information store, which is an intermediary between DNA and the cell’s functional unit, protein. The genetic information must be tailored to specific cell functions. Unnecessary information (introns) is removed from the RNA, while the vital components for proteins (exons) are retained. A research team led by Professor Dr. Mirka Uhlirova of the CECAD Cluster of Excellence for Aging Research at the University of Cologne has discovered that when the processing of this information malfunctions, a protein complex (C/EBP-Heterodimer) is activated, directing the cell into a state of rest known as cellular senescence. These findings were published under the title „Xrp1 controls the stress reaction program on spliceosome dysfunction“ in Nucleic Acid Research.
All eukaryotes (organisms in which DNA is enclosed in the cell nucleus) have a spliceosome. This is a machine that performs „splicing,“ removing introns and linking exons to form messenger RNA (mRNA). Malfunctions in the spliceosome lead to diseases known as spliceosomopathies, which can affect various tissues and manifest as retinal degeneration or myelodysplastic syndromes, a group of bone marrow disorders that affect the blood.
In the study, Uhlirova’s lab used the model organism Drosophila melanogaster, or fruit flies, to investigate how cells in a developing organism respond to spliceosome malfunctions. The scientists used a combination of genomics and functional genetics to determine the role of individual genes and their interactions. The study revealed that cells suffering from defective spliceosomal U5-snRNP (small nuclear U5 ribonucleoprotein particle) activate a stress signal response and cellular behaviors characteristic of cellular senescence. The senescence program alters crucial cell functions, preventing cell division while stimulating their secretion. Senescence is triggered to preserve damaged cells, as their immediate elimination would do more harm than good. However, the accumulation of aging cells can have negative effects on a tissue and the entire organism. Therefore, these cells are ultimately eliminated.
Uhlirova’s team identified the C/EBP-Heterodimer protein complex Xrp1/Irbp18 as the crucial driver of the stress reaction program caused by faulty splicing. The 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. One advantage of senescent cells is that they are not all eliminated at once by cell death, preserving tissue integrity. In the long run, however, these cells pose problems, as their accumulation promotes disease and aging.
„A functioning spliceosome is a prerequisite for healthy cells, tissues, and the entire organism,“ she concluded. „Further investigations into the stress signaling program we identified will be important for better deciphering the complex reactions triggered by defects in the essential machines that control gene expression – and how we can influence them.“ The findings could potentially contribute to the development of therapeutic approaches to treat diseases caused by spliceosome malfunctions.
Stanković, D., et al. (2024) Xrp1 controls the stress reaction program on spliceosome dysfunction. Nucleic Acid Research. doi.org/10.1093/nar/gkae055.