Study provides new strategies for treating different types of cancer

According to a study conducted by Karolinska Institute, an RNA molecule involved in preventing the formation of tumors can modify its structure and thus regulate the production of proteins in the cell.

Study provides new strategies for treating different types of cancer
Katja Petzold, research group leader at the Department of Medical Biochemistry and Biophysics. Image Credit: Gunnar Ask.

Published recently in the Nature journal, the outcomes can have significant clinical implications since it creates new opportunities for treating different types of cancer.

Short RNA molecules, found in the human cells and referred to as microRNAs, are key regulators of messenger RNAs (mRNA). mRNAs are molecules that code proteins—the building blocks of the human body.

The precise mechanism of this regulation continues to be a mystery, but microRNAs are known to silence the mRNA molecules and thus inhibit the production of proteins. Hence, microRNAs could be used as targets or tools for drugs.

Disturbed in many diseases

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. 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.”

Katja Petzold, Study Lead and Associate Professor, Department of Medical Biochemistry and Biophysics, Karolinska Institute

The scientists analyzed a microRNA called miR-34a that plays a vital role in cancer by indirectly controlling the activity of p53 protein, referred to as the guardian of the genome, for its potential to prevent the formation of cancer.

Variations in the p53 function are quite common in human cancers. The mRNA that codes for Sirt1, a protein that deactivates p53, is downregulated by miR-34a.

Two structurally different states

The scientists solved the dynamics and structure of miR-34a binding the mRNA molecule through nuclear magnetic resonance (NMR) and other biophysical techniques.

When the researchers quantified these dynamics, they observed that the complex is present in two structurally different states, one is moderately active with a population of 99%, and the other has enhanced activity with a population of 1%.

Since these states are in equilibrium, they can interconvert and the population of every state can be altered by external factors.

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.”

Katja Petzold, Study Lead and Associate Professor, Department of Medical Biochemistry and Biophysics, Karolinska Institute

Drugs with a new mechanism of action

The scientists were able to demonstrate that miR-34a leverages the same strategy to downregulate the production of other proteins and not just the Sirt1 protein.

We reveal the first understanding of how regulation of protein output is steered by small microRNAs based on structure and dynamics. This is important because it opens for the development of drugs with a completely new mechanism of action.”

Lorenzo Baronti, PhD Student and Study First Author, Karolinska Institute

Source:
Journal reference:

Baronti, L., et al. (2020) Base-pair conformational switch modulates miR-34a targeting of Sirt1 mRNA. Nature. doi.org/10.1038/s41586-020-2336-3.

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