tRNAs help some mRNAs get lost in translation

Editors' notes

This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility:

fact-checked

peer-reviewed publication

trusted source

proofread

Scientists have discovered that tRNAs can determine how long mRNAs exist in a cell, causing some messages to be stabilized and translated into more protein, while directing others to be degraded and limiting how much protein can be made. They published their report in Science.

The messenger RNA (mRNA)-based vaccines developed to fight the virus SARS-CoV-2 saved lives and made the nucleic acid a household name during the COVID-19 pandemic. Suddenly, everyone knew a little bit more about the molecule that helps convert genetic information into proteins.

But in addition to determining which proteins are made, mRNAs can also specify how much protein is produced.

"This regulation is important to understand, not only because we want to figure out how genes are controlled, but also because it could help us design better mRNA therapeutics," says Howard Hughes Medical Institute Investigator Joshua Mendell.

"If we're providing an mRNA to a cell, it would be great to be able to program into that sequence exactly how long it should last and exactly how much protein it should make." For example, mRNAs that produce vaccine proteins should be stable for a long time, but only a burst of mRNA is ideal when performing gene editing.

In their new study, Mendell's and Jan Erzberger's teams at the University of Texas Southwestern Medical Center report a new way that mRNA stability can be determined. They found that the process of translating mRNA information into a protein can impact the length of time that an mRNA sticks around, and an amino acid called arginine plays a crucial role.

The findings could help researchers develop new treatments for many conditions, such as obesity, cancer, and mitochondrial diseases.

Building a protein

To make a protein, the cell transcribes, or copies, genetic material from DNA into an mRNA. Then, the mRNA is translated into protein within a structure called a ribosome.

During translation, the ribosome moves along the mRNA, and as it does this, a different type of RNA called a tRNA gets involved. Different tRNAs have different three-base "anticodons" on one end that bind to complementary "codons" in the mRNA, and an amino acid at the other end. In this way, tRNAs bring over amino acids coded by the mRNA to build a protein.

As tRNAs bind to the message, they sit in different sites of the ribosome, called A, P, and E. tRNAs enter the ribosome at the A site, while a tRNA in the P-site carries the growing protein chain. The protein chain is then transferred to the amino acid on the A-site tRNA, extending it by one unit.

As that happens, the ribosome shifts, moving the newly protein-bound tRNA to the P site and the now-empty tRNA to the E site, where it prepares to leave. This leaves the A site open for a new tRNA to bring in the next amino acid. This cycle repeats until a "stop" codon tells the ribosome to halt translation.

Translating a new way to degrade mRNAs

Mendell's team knew that the sequence of the mRNA could affect its stability, but no one knew how this worked in mammalian cells. Previous research in yeast showed that when translation slows down, only one tRNA is left in the ribosome, in the P site. When the A and E sites are empty for a long time, a complex called CCR4-NOT degrades the message, and, as a result, less protein is made.

Discover the latest in science, tech, and space with over 100,000 subscribers who rely on Phys.org for daily insights. Sign up for our free newsletter and get updates on breakthroughs, innovations, and research that matter—daily or weekly.

Subscribe

"In yeast, the codon at the A site plays a major role in this process, but I surprisingly didn't detect that effect in mammalian cells," says Xiaoqiang Zhu, the postdoctoral fellow who led many of these experiments. This uncovered a key difference between yeast and mammalian cells.

Although initially disappointed in these results, Zhu's later experiments showed that the identity of the tRNA in the P site is key.

"The ribosome first moves slowly, just like it does in yeast, and that gives the CCR4-NOT complex a chance to stick a part of itself into the ribosome to see what the tRNA in the P site is," says Mendell.

In mammalian cells, the researchers saw that CCR4-NOT is most often bound to ribosomes with mRNAs that have specific arginine codons in the P site.

"It was interesting that only three out of the six codons coding for arginine were enriched, and that suggested you could make two types of messages that could be degraded at different rates," says Erzberger. He says it was assumed that arginine codons were interchangeable, but this work challenges that assumption.

Using insights from structural biology studies spearheaded by research scientist Victor Cruz, the team also pinpointed the precise architecture required for a tRNA to allow or block CCR4-NOT binding.

"This is an exciting paper with a really surprising observation," says Howard Hughes Medical Institute Investigator Rachel Green at Johns Hopkins University, who was not involved in the work.

"The complexity of the system is striking." She adds that the study explains how mRNAs can be coordinately regulated using the basics of the genetic code and protein synthesis in an unanticipated and complex manner.

The new regulatory mechanism, called P-site tRNA-mediated mRNA decay (PTMD), is a strong regulator of mitochondria, which are involved in metabolism. Because of this, the findings could someday help researchers develop new therapies for those with obesity. Mitochondria also play an important role in many other diseases, including cancer, that could be impacted by the team's insights.

The discovery of PTMD opens up many lines of investigation that the team plans to pursue. Erzberger says that other codons could have similar effects on translation, and Mendell is interested to find out more details about the regulation and physiologic role of CCR4-NOT recruitment.

"This work really showed there's an additional function that tRNAs can perform, which is not only to decode the mRNA and deliver the amino acid, but also to engage with other complexes during translation to regulate the amount of translation and the stability of the mRNA," says Mendell. "That was really exciting."

More information: Xiaoqiang Zhu et al, Specific tRNAs promote mRNA decay by recruiting the CCR4-NOT complex to translating ribosomes, Science (2024). DOI: 10.1126/science.adq8587

Journal information: Science

Provided by Howard Hughes Medical Institute