In the Language of Cells, Messenger RNA Gets Lost in Translation

A Case Western Reserve University study could open the door for new advances in gene therapy and viral vaccinations, its leader says.

Jeff Coller, Ph.D., an assistant professor in the Case Western Reserve School of Medicine's Center for RNA Molecular Biology, and his team found that messenger RNA (mRNA) predominately degrades on ribosomes, fundamentally altering a common understanding of how gene expression is controlled within the cell.

"Many genetic diseases are linked to mutations that can cause misregulation of RNA destruction, so it's important to know the when, where and how the cell normally controls the process of mRNA decay," Coller said.

The mRNA communicates genetic information from DNA to ribosomes where the information is converted to proteins. Proteins catalyze the reactions of life, and how much protein is made is critical to fine-tune the function of the cell. This means the amount of mRNA present within the cell is vital for overall cellular health.

The rates of RNA synthesis and destruction determine the overall levels of mRNA. While the details of mRNA synthesis have been studied intensely over the years, the mechanisms controlling mRNA decay remain unclear.

It previously had been thought that once an mRNA had ended its utility, it was removed from ribosomes and possibly transported to specialized structures within the cell, called P-bodies, where it is eventually destroyed.Coller's research demonstrates that decay takes place while mRNAs are associated with actively translating ribosomes.

"The data clearly indicate that sequestration into a ribosome-free state [like a P-body] is not a prerequisite for initiation of mRNA decay," Coller said. He and colleagues believe this new understanding provides an evolutionary explanation for the nature of the decay pathway and may lead to new insights into how cytoplasmic gene regulation occurs, shedding light on disease states that result when things go awry.

Coller's findings raise several interesting mechanistic questions, for instance, how mRNAs are destroyed at different rates. Some are long-lived, some short-lived. Scientists do not understand how these differences in mRNA decay rate are determined, but clearly this understanding is vital for predicting how mutations will have an impact on cellular function.

"Now that we have found that mRNAs are degraded on ribosomes, we can begin to understand how the degradation machinery interacts with ribosomes and how it is triggered to destroy the message," Coller said. "Eventually, we hope to create a rule book that would allow us to predict which mRNA is going to last only a few minutes and which will be expressed hours or days. This has a huge impact on cellular protein levels, and perhaps this understanding would lead to new advances in gene therapy and viral vaccinations."

The study, "Co-translational mRNA decay in Saccharomyces cerevisiae," is published in the latest issue of Nature. Funding was provided by the American Heart Association and the National Institutes of Health.