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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.\u00a0<\/p>\n
But in addition to determining which proteins are made, mRNAs can also specify how much protein is produced.\u00a0<\/p>\n
\u201cThis 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,\u201d says Howard Hughes Medical Institute Investigator Joshua Mendell<\/a>. \u201cIf we\u2019re 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.\u201d 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.\u00a0<\/p>\n In a new study, Mendell\u2019s and Jan Erzberger\u2019sexternal link, opens in a new tab<\/span><\/a> 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. They published their reportexternal link, opens in a new tab<\/span><\/a> on November 21, 2024.<\/p>\n 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.\u00a0<\/p>\n 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 \u201canticodons\u201d on one end that bind to complementary \u201ccodons\u201d 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.\u00a0<\/p>\n 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 \u201cstop\u201d codon tells the ribosome to halt translation.\u00a0<\/p>\n Mendell\u2019s 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. \u201cIn yeast, the codon at the A site plays a major role in this process, but I surprisingly didn\u2019t detect that effect in mammalian cells,\u201d says Xiaoqiang Zhu, the postdoctoral fellow who led many of these experiments. This uncovered a key difference between yeast and mammalian cells.\u00a0<\/p>\n Although initially disappointed in these results, Zhu\u2019s later experiments showed that the identity of the tRNA in the P site is key. \u201cThe 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,\u201d says Mendell.\u00a0<\/p>\n 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. \u201cIt 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,\u201d 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 Cruzexternal link, opens in a new tab<\/span><\/a>, the team also pinpointed the precise architecture required for a tRNA to allow or block CCR4-NOT binding.\u00a0<\/p>\n \u201cThis is an exciting paper with a really surprising observation,\u201d says Howard Hughes Medical Institute Investigator Rachel Green at Johns Hopkins University, who was not involved in the work. \u201cThe complexity of the system is striking.\u201d 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. \u00a0<\/p>\n 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\u2019s insights.\u00a0<\/p>\n 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.\u00a0<\/p>\n \u201cThis work really showed there\u2019s 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,\u201d says Mendell. \u201cThat was really exciting.\u201d<\/p>\n ####<\/strong><\/p>\n Citation:\u00a0<\/strong><\/p>\n Xiaoqiang Zhu, Victor Emmanuel Cruz, He Zhang, Jan P. Erzberger, Joshua T. Mendell. \u201cSpecific tRNAs promote mRNA decay by recruiting the CCR4-NOT complex to translating ribosomes.\u201d Science.\u00a0<\/em>Building a protein<\/h3>\n
Translating a new way to degrade mRNAs<\/h3>\n
https:\/\/www.science.org\/doi\/10.1126\/science.adq8587external link, opens in a new tab<\/span><\/a><\/p>\n<\/p><\/div>\n