Why mRNA Lifetime Is Linked to Its Translation Efficiency

In a study published today in Science, Ludwig-Maximilians-Universitaet (LMU) researchers show why mRNA blueprints that are more difficult to decipher have shorter lifetimes than the rest.

The control of gene expression is a fundamental component of living systems. Because the set of proteins synthesized in a cell defines its structure and biochemical capacities, every step in the process must be tightly regulated. One of the modules of this regulatory system is dedicated to the timely destruction of mRNAs in response to changing conditions.

Researchers have now worked out the detailed structure of a protein complex that is involved in mRNA degradation and have dissected its mode of action. The results of the new study, published today in Science, explain how and why the lifetime of an mRNA molecule is linked to the rate of synthesis of the protein it encodes.

“Statistical data had already revealed that the lifetime of an mRNA is correlated with speed of the ribosome during synthesis of its protein product,” says first author Robert Buschauer. “But the molecular basis for this relationship was completely unknown.”

The efficiency of protein synthesis largely depends on how well the ribosome can read the instructions encoded in the nucleotide sequences of mRNAs. Triplet sequences of nucleotides called codons specify the order in which the different amino acids that make up the protein are linked together. Each amino acid is delivered to the ribosome by an adaptor molecule called a tRNA, which is also equipped with a nucleotide triplet (an anticodon) that recognizes its counterpart in the mRNA. This interaction enables the tRNA’s amino-acid cargo to be slotted into the correct position in the growing protein.

Most amino acids are specified by several nucleotide triplets, which are read with varying efficiencies by the ribosome. If a given triplet is difficult to read, the ribosome takes longer to select the appropriate tRNA with the required amino acid. In the new study, researchers found that an important protein for RNA degradation is able to interact with the ribosome only when the tRNA binding site is unoccupied, making the likelihood of degradation increase with the number of less efficient codons.

The destruction of mRNAs is an essential process whose components differ very little between yeast and human cells. Any errors that occur can give rise to neurodegenerative diseases, cancers, or other serious disorders. A better understanding of the underlying mechanisms is therefore a prerequisite for the development of more effective therapies.