Hayadan > Dynamic, sophisticated and sensitive to the environment: this is how the mRNA formulates its instructions to the ribosome

Dynamic, sophisticated and sensitive to the environment: this is how the mRNA formulates its instructions to the ribosome

Researchers at the Technion discovered a new mechanism in the control of protein production by the ribosome: an enzyme that edits the mRNA and regulates its activity according to the organism's needs. The article presents editing processes similar to those used by the companies Pfizer and Moderna in the development of the new mRNA vaccines

3. In the diagram: on the left: the vaccines. mRNA vaccines are based on introducing artificial mRNA into cells so that it will serve as a template for building the viral protein that will activate the immune system. Shortly after the entry of the mRNA molecules into the cell, they begin to initiate the production of the immune proteins required by the cell. mRNA contains several chemical changes, which improve its activity in the cell. Right: the natural mechanism. The study published in Nucleic Acids Research shows how similar chemical modifications, naturally present in mRNA, serve as binding sites for regulatory factors. This link affects the activity of the ribosome and thus enables the production of proteins in more precise quantities and in accordance with the needs of the organism. — In the diagram: on the left: the vaccines. mRNA vaccines are based on introducing artificial mRNA into cells so that it will serve as a template for building the viral protein that will activate the immune system. Shortly after the entry of the mRNA molecules into the cell, they begin to initiate the production of the immune proteins required by the cell. mRNA contains several chemical changes, which improve its activity in the cell. Right: the natural mechanism. The study published in Nucleic Acids Research shows how similar chemical modifications, naturally present in mRNA, serve as binding sites for regulatory factors. This link affects the activity of the ribosome and thus enables the production of proteins in more precise quantities and in accordance with the needs of the organism.

Researchers at the Technion discovered an unknown mechanism that controls the creation of proteins in the cell. This mechanism utilizes chemical changes on the mRNA to affect the rate at which the ribosome, the cellular protein factory, makes the proteins. The researchers, Prof. Yoav Araba and doctoral student Ofri Levy from the Faculty of Biology, published the discovery in the journal Nucleic Acids Research.

The control of genetic expression is responsible for translating the genetic code (written in DNA) into proteins adapted to their purpose in the specific tissue, taking into account the changing environmental conditions. "If DNA is the cookbook," says Ofri Levy, "then the baker is the ribosome - the protein factory in the cell." The main mediator in the process is the mRNA molecule, which transfers the "recipe" from the DNA to the ribosome. Correct interaction between the mRNA and the ribosome is essential for the integrity of the proteins and their quality."

It has been known for several years that the mRNA does not transmit the instructions from the DNA literally, but undergoes many changes along the way. These chemical changes made headlines recently in the context of the corona vaccines; The vaccines of the companies Pfizer and Moderna are based on the introduction of artificial mRNA into the body so that it leads to the creation of immune proteins within the cells of our body. However, since the cell treats the mRNA as a foreign body, it tends to attack it, and the rapid degradation of the mRNA does not leave it enough time to produce the essential proteins. To face this challenge the two companies combined their mRNA molecules Changes that mimic natural changes that occur in the body. These changes do allow the artificial molecule to survive and function long enough to produce the protein from the virus.

According to Prof. Araba, "The relationship between mRNA and protein creation is a process that has occupied us for many years, and we focus on the effect of mRNA on the construction of proteins and their stability. We are trying to understand the 'conversation' in which the mThe ribosome has something to produce for the cell. We conduct the basic research on the yeast (Saccharomyces cerevisiae), also known to us as baking yeast, and we have a good basis to assume that what happens in the yeast Very relevant to what happens in the human body. "

In a previous article, published in July 2019 in the journal PLOS Biology, Levy and Prof. Araba presented a new role for certain enzymes common in all kingdoms of life. The researchers discovered that these enzymes are significant control factors in the production of proteins - a role that was not known until the publication of that article. To fulfill this role, these enzymes bind to mRNA and regulate the amount of mRNA molecules available to the ribosome.

In the current study, Levy and Prof. Araba delved into the question of how those enzymes identify the mRNA within the cell components. They discovered that the answer lies in a unique chemical change in the mRNA. This change, called pseudouridine, is created in different places on the mRNA; Control factors detect this change and schedule ribosome activity accordingly.

To prove the importance of the aforementioned change, the researchers developed a method based on CRISPR/Cas9, which allowed them to "surgically" remove the pseudouridine without any other damage to the cells. Indeed, in the absence of pseudouridine, control over protein production was lost. According to Levy, "Like many scientists in the world, we also owe a huge thank you to Prof. Emmanuel Charpentier and Prof. Jennifer Daudna for the dramatic breakthrough in the development of CRISPR/Cas9 technology."

Charpentier and Daudena received the Harvey Prize from the Technion on November 3, 2019 and a year later, on December 10, 2020, they were awarded the Nobel Prize in Chemistry for the development of the revolutionary technology that makes it possible to edit, repair and rewrite DNA. "This technology," says Levy, "allowed us to advance our research with unprecedented speed and precision."

Technion researchers estimate that this is the case In an evolutionarily conserved mechanism, which exists throughout the animal world. Since this mechanism is sensitive to changes in the environment, it provides the mRNA molecules Guidelines adapted to the environmental situation And thus leads the ribosome to optimal production of proteins.

As mentioned, one of the important tasks facing the companies Pfizer and Moderna was to improve the activity of the artificial mRNA in the human body, so they introduced a change to the "immune" mRNA that is very similar to pseudouridine. "We still don't know if the control factors we discovered also know how to recognize the existing change in the artificial mRNA," says Prof. Araba. "If they do know, this may open up further possibilities for improving the activity of them and to produce larger amounts of protein. "

Beyond the current research and its implications, Prof. Araba says, "Our discovery illustrates HThe return of basic research in the development of sophisticated medical treatments and innovative vaccines. The public and the media are mainly thirsty for publications about developments and applied science, but without a strong and broad infrastructure of basic research - in directions whose applied horizon is not always clear - we would not have seen such dramatic breakthroughs in diagnosis, treatment and vaccines as well as in areas of life outside the world of medicine."

The research was funded by the National Science Foundation (ISF). Ofri Levy is the winner of the Jacobs Scholarship for outstanding students.

For the full article b- Nucleic Acids Researchclick here

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