A team headed by scientists at the University of Birmingham has come a step closer to discovering the purpose of a distinctive set of modifications discovered at the start of messenger RNA, which have long been a fundamental mystery in molecular biology.
Messenger RNAs (mRNAs) are crucial 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 critical role in the way the messenger RNA produces proteins.
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 unidentifiable.
Although scientists have known about these mRNA modifications for more than 45 years, it has not been properly understood. This is because scientists have not been able to demonstrate what happens when this methylation in mRNA is knocked out or removed from animal model organisms.
Researchers from the Universities of Birmingham, Oxford,Nottingham, and Wilmingham City University succeeded in constructing a knockout model using fruit flies (Drosophila) by eliminating two key genes. That means they were able to demonstrate what happens when the flies do not have the two enzymes used in the methylation process.
The two enzymes played an important role in the animals reward learning process, although the modified flies did not survive. These flies showed a defect in their ability to learn the association of a specific odour with a sugar reward.
Dr Matthias Soller, the lead author of the University of Birmingham''s Biosciences, claims that mRNA modifications have significant roles in the brain. Even if these flies are alive, they aren''t quite capable of developing essential survival skills.
The research focuses on the work previously undertaken by one of the papers co-authors, Professor Rupert Fray, at the University of Nottingham, who discovered that cap modifications were extremely beneficial for mice.
These modifications aided the transport of the mRNAs to synapse the location of communication between neurons, according to the team.
This learning phenotype, according to Professor Scott Waddell of the Centre for Neural Circuits and Behaviour at Oxford University, has raised many new questions. While we do not yet know the scope of the underlying neuronal dysfunction, this latter technique is comparable to the Fragile X Mental Retardation Protein FMRP, which includes RNA biology and is known to produce defects in synapse development and plasticity.
Dr. Irmgard Haussmann of Birmingham City University notes that studying cap modifications is extremely challenging and there are even further technical obstacles to overcome when it comes to studying changes in specific mRNAs.
This is particularly applicable as SARS and other viruses that have their own cap methylation enzyme, but it is not really understood how this affects virus-host interactions, according to 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 depth the mechanism by which the modified mRNA is able to influence protein expression, which is beneficial to reward learning and virus propagation.