Targeted Destruction of Messenger RNA Regulates Cellular Protein Synthesis

Messenger RNA carries the instructions genes from the nucleus of a cell into the cytoplasm where it teams up with ribosomes to manufacture protein. As long as the mRNA remains functional, protein synthesis can continue. It was not known how the cell controlled the amount of protein to make.

Investigators at Case Western Reserve University (Cleveland, OH, USA) and Johns Hopkins University (Baltimore, MD, USA) have now proposed a mechanism to explain how levels of cellular protein synthesis are controlled.

The master regulator is the enzyme called DEAD-box protein Dhh1p. DEAD box proteins are involved in an assortment of metabolic processes that typically involve RNAs, but in some cases also other nucleic acids. They are highly conserved in nine motifs and can be found in most prokaryotes and eukaryotes, but not all. Many organisms, including humans, contain DEAD-box helicases, which are involved in RNA metabolism.

The investigators reported in the September 15, 2016, online edition of the journal Cell that Dhh1p physically interacted with ribosomes in vivo. It was a sensor of codon optimality that targeted an mRNA for decay. Messenger RNAs whose translation elongation rate was slowed by inclusion of non-optimal codons were specifically degraded in a Dhh1p-dependent manner. Biochemical experiments showed that Dhh1p was preferentially associated with mRNAs with suboptimal codon choice. These effects on mRNA decay were sensitive to the number of slow-moving ribosomes on an mRNA.

“Our study provides a new way to look at the genetic code,” said senior author Dr. Jeff Coller, director of the center for RNA molecular biology at Case Western Reserve University. “We are so used to looking at how DNA mutations cause a change in protein function. We must also consider how enzymes like Dhh1p sense the speed at which ribosomes interpret the genetic code. Now I can look at the genetic code in terms of speed and rate, and with reasonable accuracy predict how much protein is going to come from a gene. There is huge application for that in human biologics, proteins that are easily taken by injection. There are rare genetic diseases attributed to RNA being read too slow or too fast. We can now manipulate this process to dial up or down protein expression. The speed at which the ribosome reads the genetic code and is sensed by Dhh1p could open up a new set of mutation types that could indicate disease states we are unaware of today.”

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Case Western Reserve University
Johns Hopkins University