The Impact of Spliceosome Dysfunction on Cellular Senescence and Aging Program

2024-02-03 05:42:27

The genetic material, in the form of DNA, contains the essential information for the proper functioning of every human and animal cell. From this database is created RNA, an intermediary between DNA and protein, the functional unit of the cell. During this process the genetic information must be adapted to specific functions of the cell. Unnecessary information (introns) is cut from the RNA and the important components for proteins (exons) are preserved. A team of researchers led by Professor Dr. Mirka Olirova from the CECAD aging research excellence cluster of the University of Cologne has now discovered that if the processing of this information no longer works properly, a protein complex (C/EBP heterodimer) is activated and directs the cell towards a dormant state, known as cellular senescence. The results appeared Under the heading ‘Xrp1 controls the stress response program for spliceosome dysfunction’ b Nucleic acid research.

All eukaryotes (ie organisms where the DNA is enclosed within the cell nucleus) have a spliceosome. It is a machine that performs ‘splicing’, removing introns and splicing exons to create messenger RNA (mRNA). Malfunctions in the spliceosome lead to diseases known as spliceosomopathies, which can affect many different tissues and manifest as retinal degeneration or myelodysplastic syndrome, 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 study how cells within a developing organism respond to spliceosome dysfunction. The 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 (U5 small nuclear ribonucleoprotein particle) activate a stress signaling response and cellular behaviors typical of cellular senescence. The aging program changes crucial functions of the cells. This prevents the cells from dividing while stimulating their secretion. Senescence is activated to preserve damaged cells, as their immediate elimination would cause more harm than good. However, the accumulation of senescent cells can have a negative effect on the tissue as well as the entire organism. Therefore, these cells are eventually eliminated.

Uhlirova’s team identified the C/EBP-heterodimer protein complex, Xrp1/Irbp18, as the critical driver of the stress response program induced by defective splicing. Upregulation of Xrp1/Irbp18 in damaged cells led to increased protein production and induced a senescence-like state. “Aging is a double-edged sword,” Olirova said. One advantage of senescent cells is that they are not all eliminated by cell death at the same time, thus preserving the integrity of the tissue. After all, partially intact tissue is better than none. However, these cells create problems in the long term, as their accumulation promotes disease and aging.

“A functioning spliceosome is a prerequisite for healthy cells, tissue and the entire organism,” she concluded. “Further investigation of the stress signaling program we identified will be important to further unravel the complex responses triggered by defects in the vital machinery that controls 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 dysfunction.