A team led by scientists has come a step closer to uncovering the purpose of a distinctive set of modifications found at the beginning of messenger RNA which have long remained a fundamental mystery in molecular biology.
Messenger RNAs (mRNAs) are vital for protein production. Their specific structure at the beginning of the chain, called a cap, has two main functions. It protects the mRNA from breaking down, but also it plays a key role in the way the messenger RNA produces proteins.
In addition to the cap structure, the first few nucleotides of an mRNA can carry small decorations called methylation. These occur in animals as well as in some of their parasites like SARS viruses and trypanosomes, but their purpose has remained enigmatic.
Although scientists have known about these mRNA modification for more than 45 years, its effect on the function of mRNA has not been well understood. This is because scientists have not been able to show what happens when this methylation in mRNA is ‘knocked out’, or removed from animal model organisms.
In a new study, published in Nature Communications, researchers succeeded in creating a knockout model using fruit flies (Drosophila) by removing two key genes. That means they were able to show what happens when the flies don’t have the two enzymes used in the methylation process.
They found that, although the modified flies did still live, 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 odor with a sugar reward.
Lead author 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 previous work that 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.
The senior author 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.”
Another author adds: “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,” adds another author.
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.
https://www.nature.com/articles/s41467-022-28549-5
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fcmtr-cap-adjacent-2&filter=22
Mysterious messenger RNA modifications in reward learning
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