• Mystery behind mRNA Modifications begins to Unravel

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Mystery behind mRNA Modifications begins to Unravel

Mar 25 2022

Research led scientists at the University of Birmingham, investigating the purpose of modifications found at the beginning of messenger RNA chains have been able to come up with insights into their purpose which were previously unknown.

Messenger RNAs (mRNAs), vital for protein production, are protected by a cap structure at the beginning of the chain which also influence how messenger RNA produces proteins. It is the first few nucleotides of the cap structure of an mRNA which carry the modifications called methylation. These occur in animals as well as in some of their parasites like SARS viruses and trypanosomes.

By succeeding in creating a ‘knockout model’ which removed two key genes from fruit flies (Drosophila), researchers from the Universities of Birmingham, Oxford, Nottingham and Warwick were able to show that the two enzymes played an important role in the animals’ reward learning process. These flies showed a defect in their ability to learn the association of a specific odour with a sugar reward, highlighting what happened when the flies don’t have the two enzymes used in the methylation process.

Lead author Dr Matthias Soller from the School of Biosciences at the University of Birmingham says:

“The study shows us that mRNA modifications have important functions in the brain. Even though these flies are alive, they are not very capable of learning essential survival skills.”

 The research builds on work previously done by one of the paper’s co-authors, Professor Rupert Fray at the University of Nottingham, who found that cap modifications are highly dynamic in mice.

The team discovered that these modifications played a role in transporting the mRNAs to synapses – the site of communication between neurons.

Professor Scott Waddell from the Centre for Neural Circuits and Behaviour at Oxford University said: “This learning phenotype opens many new questions. Although we do not yet know the detailed nature of the underlying neuronal dysfunction, it is reminiscent of the genetic disease associated with Fragile X Mental Retardation Protein FMRP, which also involves RNA biology and is known to produce defects in synapse development and plasticity.”

Dr Irmgard Haussmann from Birmingham City University added: “Analysing the cap modifications is very challenging and further technical hurdles need to be taken to look at modifications in specific mRNAs.”

 “This is highly relevant as SARS and other viruses that have their own cap methylation enzyme, but it is not really understood what role this plays in virus-host interactions,” commented Dr Nathan Archer from the University of Nottingham School of Veterinary Medicine and Sciences.

The next step for the team will be to investigate in more detail the mechanism by which the modified mRNA is able to influence protein expression relevant to reward learning and virus propagation.

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