UNC team explores mRNA breakdown

In every cell in our body, messenger RNA – “mRNA” – is responsible for the production of proteins crucial for life. What happens to these important molecules, once their job is done? They must be degraded, or else they make too much protein and stop cells from working correctly.

In a paper in the March edition of Molecular Cell, a team of scientists from UNC Chapel Hill outlines exactly how this mRNA degradation occurs. The researchers, led by William Marzluff – Kenan Distinguished Professor of biochemistry and biophysics at the UNC School of Medicine – describe how a complex of proteins, known as the “exosome,” is responsible for mRNA’s breakdown.

“Improper formation of the exosome is lethal. Cells die if the exosome can’t be made,” Marzluff said.

A delicate balance must be struck when the exosome breaks down mRNA: The exosome must degrade the mRNA molecules, but not too quickly. If mRNA is destroyed too soon, a cell might not make enough protein to function correctly.

In essence, too much or too little mRNA means too much or too little protein, which can spell trouble for a cell.

“Excess proteins likely bind to DNA and shut down genes that shouldn’t be shut down. If you don’t make enough proteins, it can result in DNA damage, as well as expression of genes that should be shut off,” said Marzluff.

Marzluff and his team were able to determine the role of the exosome in the breakdown of mRNA by using what is known as “high-throughput sequencing.” Through this, researchers and scientists can use modern technology to quickly and cheaply scan of thousands or even millions of molecules at a time, in order to determine their genetic structure.

“Normally, we would isolate and sequence one mRNA molecule at a time, and only some of them are the interesting ones; the ones we caught while they were partially degraded,” Marzluff said. “Over five years, we were only able to get a hundred of these.”

But with high-throughput sequencing, the team has been able to identify thousands of degrading mRNAs, and also the rate at which the exosome breaks them down.

“These new sequencers allow us to sequence more than a million molecules at once, and in one day, we got several thousand that were in the process of being degraded,” Marzluff said.

“I should mention that the analysis of the millions of sequences is very challenging, and that was solved by the two computer scientists we worked with.”

Marzluff and his team want to better understand how the cell signals the exosome to begin degrading mRNA, and what other proteins besides the exosome are required.

“There is also a signal (to begin mRNA breakdown) from the nucleus of the cell to the cytoplasm of the cell, and we don’t yet know how that signal is transmitted from the nucleus to the cytoplasm,” Marzluff said.

“We will find out what other proteins are required and hopefully how the signals for degradation are transmitted.”