Researchers have uncovered a new mechanism in the protein production process that may offer a promising avenue for cancer treatment, while also shedding light on neurodegenerative diseases. The study, led by scientists at Goethe University Frankfurt, reveals how a subtle interference in cellular splicing could target cancer cells without affecting healthy tissue.
Genes as Life’s Building Instructions
Genes carry essential instructions for life, directing cells on how to assemble amino acids to create specific proteins. The human genome contains about 20,000 such instructions, yet our cells can produce hundreds of thousands of different proteins. This diversity is possible due to a process called “splicing,” according to Professor Ivan Đikić from the Institute of Biochemistry II at Goethe University Frankfurt.
The Role of Splicing in Protein Diversity
When cells need a particular protein, they copy the relevant genetic instructions within the cell nucleus. During splicing, these copies undergo modifications: the spliceosome, a cellular editing complex, removes certain segments. The end result varies based on which parts are cut out, producing different blueprints for various proteins.
“The spliceosome is made up of multiple components that ensure the production of functional proteins, which are essential for cellular life,” explains Prof. Đikić. “If this complex is disrupted, it can lead to cell death. Because of this, spliceosome inhibitors are being explored as potential anti-cancer drugs.”
Splicing Accuracy and Cancer Treatment Challenges
However, a significant challenge with current spliceosome inhibitors is that they affect not only cancer cells but also healthy cells, leading to severe side effects. The complete blockade of the spliceosome disrupts the protein production process, which is vital for all cells.
In an effort to address this, an international team of researchers has identified a more precise mechanism that could subtly interfere with the splicing process. Their focus was on a specific part of the spliceosome, a complex made up of three subunits known as U4, U5, and U6.
New Findings from Zebrafish Experiments
The team conducted experiments on zebrafish and used mathematical models to explore the function of these spliceosome subunits. They discovered that these subunits are stabilized by a protein called USP39. If USP39 is missing, or if the subunits are mutated, the stability of the spliceosome is compromised, which reduces splicing precision.
Under normal conditions, U4/U6.U5 ensures that loose ends of the genetic transcript are reconnected accurately after splicing. Without USP39, this reconnection is delayed, increasing the chance of incorrect edits. “Our computer simulations confirmed that this leads to improperly edited transcripts, which result in the production of dysfunctional proteins,” says Dr. Prieto-Garcia, a co-author of the study.
These faulty proteins accumulate and can form aggregates within cells. Although cells have a waste disposal system to eliminate defective molecules, this mechanism was overwhelmed in the absence of USP39, eventually leading to cell death, particularly in the zebrafish retina.
Implications for Neurodegenerative Diseases and Cancer
“The discovery of this mechanism was unexpected,” notes Prof. Đikić. Researchers believe that similar processes could explain the death of retinal cells in patients with retinitis pigmentosa. Moreover, defective splicing variants might contribute to neurodegenerative diseases like Alzheimer’s and Parkinson’s.
Interestingly, this mechanism could also be exploited for cancer treatment. Some aggressive tumors produce high levels of USP39 and other splicing factors due to their rapid cell division rates. These cancer cells rely on precise splicing to sustain their growth. “By blocking USP39 in these cancer cells, we might selectively kill them,” Đikić explains. “Healthy cells, which divide at a much slower rate, would be less affected. This is a strategy we are actively exploring.”
Future Therapeutic Potential
The study opens up new possibilities for targeted cancer therapies that minimize damage to healthy cells. By focusing on the splicing mechanism, researchers hope to develop treatments that specifically disrupt the protein production of cancer cells, potentially leading to fewer side effects compared to traditional therapies.
The team’s findings not only pave the way for new cancer treatment approaches but also offer insights into the underlying mechanisms of various diseases, including neurodegenerative disorders.
This groundbreaking research highlights the delicate balance of cellular processes and the potential for innovative treatments that target the unique vulnerabilities of cancer cells, while sparing healthy ones. Further studies are needed to explore the therapeutic applications of this discovery.
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