4. Nov. 2022

This discovery offers a new way of defence against RNA viruses in humans

Richard Stefl from CEITEC Masaryk University (MU) and Petr Svoboda from the Institute of Molecular Genetics of the Czech Academy of Sciences (IMG CAS) and their colleagues have revealed the unique mechanism of action of mammalian Dicer. Dicer is an RNA-cutting enzyme that is essential for the regulation of gene activities in cells. The research team described how Dicer could be reactivated to serve as an antiviral enzyme. This discovery provides previously unexploited opportunities for the design of new defence mechanisms against RNA viruses in humans. The research results were published on 3 November 2022 in the prestigious scientific journal Molecular Cell.

The way Dicer cuts and trims RNA and how this affects gene silencing and antiviral immunity in lower organisms is well known. It combines two enzymatic activities, the helicase activity that is responsible for feeding RNA and the nuclease activity that is responsible for cutting it, forming a very efficient enzyme. The first function, feeding RNA into the enzyme, has altered during evolution despite conservation of the helicase catalytic centre, with far-reaching consequences, such as the loss of Dicer’s antiviral properties.

In the published article, researchers have solved a decade-old puzzle and described an alternative way in which mammalian Dicer selects and feeds RNA for subsequent cutting. To solve this conundrum, scientists analysed the structure of this enzyme with or without RNA using cryo-electron microscopy and also studied genetically engineered mice that would carry specific mutations in the helicase domain of the enzyme. Their work revealed that the helicase domain acquired a new unexpected critical role in making regulatory microRNAs and why it does not cut viral RNA. Scientists showed that during the evolution of vertebrates, the feeding arm became locked in a specific position, in which Dicer favours processing microRNAs but not other RNA molecules. When the feeding arm was unlocked by a mutation, the enzyme also began to cut other RNA molecules efficiently. However, the enzyme began producing microRNAs imprecisely, and mice with only this modified enzyme would die[BC(1] .

This work thus explains how the mammalian Dicer enzyme is adapted for making regulatory microRNAs. The research team provided a new model for microRNA biogenesis in mammals and offer a plausible explanation for why Dicer maintained its dedication during hundreds of millions of years of evolution leading to mammals. Uncovering the structural basis of the Dicer mechanism may help to find a strategy to reactivate the ancestral antiviral activity of this enzyme in the near future.

This work was a joint effort spearheaded by the laboratories of Richard Stefl from CEITEC Masaryk University and Petr Svoboda from the Institute of Molecular Genetics (IMG) of the Czech Academy of Sciences and included collaboration with Donal O’ Carrol from the University of Edinburgh and Carrie Bernecky from the Institute of Science and Technology Austria. This research was financed by the ERC Consolidator Grant of Richard Stefl and ERC Consolidator Grant of Petr Svoboda.

Read the original article in Mollecular Cell HERE



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