How disrupted cell processes promote cancer

Researchers at the University of Bern, together with scientists from Stanford University and the European Molecular Biology Laboratory (EMBL), have discovered a new cellular mechanism that controls the stability of messenger RNA (mRNA) in cells. When this mechanism is disrupted, tumors can grow more quickly. The findings open new possibilities for cancer therapy.

Each cell contains thousands of proteins, each of which performs a specific function within the cell. To make a protein, a gene must first be translated into messenger RNA (mRNA). This then serves as a blueprint to produce the protein by ribosomes, the 'protein factories' of cells. For example, the RNA (ribonucleic acid) in the mRNA vaccines that ended the coronavirus pandemic was chemically modified - a strategy that won the Nobel Prize in Medicine in 2023. Such modifications also occur naturally in RNA and influence how stable the 'protein blueprint' is. More stable mRNA means that the gene is more active and more of a particular protein is produced. RNA changes have been repeatedly observed in cancer and neurodegenerative diseases. However, it has been unclear how this is related to the development of these diseases and therefore could not be used for medical treatment.

A team led by Prof. Dr. Sebastian Leidel from the Department of Chemistry, Biochemistry and Pharmaceutical Sciences at the University of Bern, in collaboration with researchers from Stanford University and the European Molecular Biology Laboratory (EMBL), has now gained new insights into this question. They have discovered a previously unknown mechanism by which the interaction of two such RNA modifications during protein production controls the degradation of mRNA. The study was supported by the Swiss National Science Foundation's National Centre of Competence in Research (NCCR) RNA & Disease and was recently published in the journal Cell.

An unexpected function

The most common modification of mRNA is N⁶-methyladenosine – m⁶A for short – and is investigated in over 2,500 scientific studies every year. The most important function of m⁶A is to control how quickly mRNA is degraded. Although the role of m⁶A was undisputed, the underlying mechanism was unknown. The Bernese researchers have now discovered that the ribosomes that produce proteins ‘stumble’ and ‘collide’ when reading the m⁶A modification on the mRNA. This causes the ribosomes to trigger the accelerated degradation of mRNA. “We can measure how quickly ribosomes read the mRNA to assemble proteins. To our surprise, we saw that ribosomes have difficulty reading the m⁶A modification on the mRNA”, explains Prof. Sebastian Leidel, lead author of the study.

The researchers further included transfer RNAs (tRNAs) in their investigation. tRNAs play an important role in translating mRNA into a protein and are themselves chemically modified. A specific chemical signature is required on the tRNA to read m⁶A. “If this signature is missing on the tRNA, the mRNA with m⁶A modifications becomes very unstable and ribosome collisions occur”, says Leidel. Cells therefore use the interaction between mRNA modification and tRNA modification to precisely regulate the rate at which mRNA is degraded. This is particularly important because both too much and too little gene activity can lead to disease. The research teams were able to show that mRNAs for important signaling molecules that play a major role in cancer development are stabilized. As a result, signaling proteins are efficiently produced and contribute to the spread of cancer cells.

A new approach to cancer therapy

The new findings could help develop new cancer therapies. “Our research in public databases has shown that in almost all types of cancer, the ratio of this specific chemical signature to m⁶A was disrupted. The more the tRNAs were modified in relation to mRNA, the worse the prognosis for patients”, Leidel summarizes. Dr Bastian Linder from EMBL and one of the study's lead authors adds: “This completely new approach to gene regulation also opens up new possibilities for treating diseases caused by changes in gene activity, such as cancer”. Linder therefore founded the company Umlaut.bio to exploit tRNA modifications as drug targets. The aim is to ensure that the new findings from basic research benefit patients as quickly as possible.

The value of scientific cooperation

"Our study is an excellent example of the importance of collaboration in science," says Leidel. "Our collaborators were able to determine exactly where m6A is located in the mRNA, and we were able to measure how fast the ribosomes read the mRNA at these sites. We had the same idea independently, but we couldn't test it on our own. It was only when we combined our data that we discovered the new mechanism", concludes Leidel.

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