New understanding of RNA movements can be used in cancer treatment

Posted on 2020-06-22

New findings of an RNA molecule involved in preventing tumor formation may open for new strategies to treat different types of cancer. The molecule can change its structure and thus control protein production in the cell. This research was published from the Karolinska Institutet in Nature.

What are microRNA?

Ribonucleic acid (RNA) is an essential molecule encoding genetic information in cells. Messenger RNA transmits genetic information to the proteins and acts as a template for protein synthesis. Approximately 2% of RNA molecules will serve as protein templates, and the remaining are microRNAs. MicroRNAs are between 18 and 25 nucleotides long, and play a key role in the regulation of gene expression. They comprise about 2,500 molecules known for humans so far.

The exact mechanism of this regulation remains elusive, however, it is known that microRNAs are able to silence mRNA molecules, preventing protein production. This means they have the potential to be used as tools or targets for drugs.

MicroRNAs bind proteins from the Argonaute family (AGO), forming a small microRNA-AGO complex that functions to inhibit protein production. The microRNA component provides specificity and determines the region of mRNA that the complex binds. The Argonaute protein directly inhibits protein production via i) cleaving the mRNA, or ii) blocking sites for protein synthesis. Thus, if a microRNA-AGO complex binds to mRNA, its corresponding protein will not be produced and gene expression can effectively be silenced.

Using microRNA to treat cancer

Katja Petzold, Associate Professor at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet said, “It’s important to increase our understanding of how microRNA regulates protein production because this process is disturbed in many different types of diseases, including cancer". Katja led the study in Sweden.

"We show for the first time that a microRNA-mRNA complex has a structure that changes and that this movement has an effect on the biological outcome, i.e. the amount of protein produced in the cell.”

The study consisted of research into a microRNA known as miR-34a. This plays an important role in cancer by indirectly regulating the activity of the p53 protein. miR-34a downregulates the mRNA that codes for SIRT1. This is a protein that deactivates p53. Changes in the function of p53 are common in human cancers, and the protein is extremely important for its ability to prevent cancer formation.

Using biophysical methods like Nuclear Magnetic Resonance (NMR), the researchers discovered the structure and dynamics of miR-34a binding the mRNA molecule. When measuring the dynamics, the study found that the complex exists in two structurally different states. One was moderately active with a population of 99%, and one with enhanced activity contained a population of 1%. The population of these states can be modified by external factors. As they are in equilibrium, they can also interconvert.

Katja explained, "Once we find out how to turn the switch, we can use this in the clinic as a drug to control the production of specific proteins.”

MiR-34a was also seen to use the same strategy to downregulate the production of other proteins.

"We reveal the first understanding of how regulation of protein output is steered by small microRNAs based on structure and dynamics," noted Lorenzo Baronti, a Ph.D. student in Katja Petzold's study group. "This is important because it opens for the development of drugs with a completely new mechanism of action."

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New understanding of RNA movements can be used in cancer treatment

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