In a groundbreaking study published in Science, a team of researchers including Xiaoqiang Zhu, Ph.D., Jan P. Erzberger, Ph.D., Joshua T. Mendell, M.D., Ph.D., and Victor Emmanuel Cruz, Ph.D., has unveiled a critical role played by transfer RNAs in the regulation of messenger RNA stability, thereby illuminating new dimensions of cellular activity.
DALLAS – Nov. 21, 2024 – A team from UT Southwestern Medical Center has revealed that transfer RNA (tRNA), often recognized for its essential function in decoding the genetic script that leads to protein synthesis, is also pivotal in determining the longevity of these instructions within cells. This innovative research, detailed in the esteemed journal Science, advances the understanding of the dynamic processes governing the degradation of messenger RNA (mRNA), a crucial regulatory mechanism for gene expression. These findings hold promise for developing new therapeutic strategies targeting a multitude of health issues, including obesity and cancer.
“Our work revealed a fundamental role for tRNAs in controlling mRNA stability and connecting the sequence of an mRNA to its rate of decay,” explained Joshua T. Mendell, M.D., Ph.D., a Professor of Molecular Biology at UT Southwestern and a distinguished Investigator at the Howard Hughes Medical Institute. He co-led this pivotal study alongside Jan P. Erzberger, Ph.D., an Associate Professor of Biophysics, and Xiaoqiang Zhu, Ph.D., an Assistant Instructor of Molecular Biology.
The study’s accompanying image illustrates the intricate molecular architecture of a ribosome (depicted in blue and yellow), the cellular machinery responsible for protein synthesis, as it decodes the genetic information held within messenger RNA (mRNA). Within this complex, a transfer RNA (colored red) actively recruits a component of the CCR4-NOT complex (shown in green) to facilitate the degradation of the associated mRNA, showcasing the interplay between these molecular players.
Dr. Mendell articulated the significance of mRNA persistence, stating that the duration each mRNA transcript remains in the cell critically influences protein synthesis levels, which fundamentally affects cellular functions. For instance, mRNA vaccines, utilized by billions globally to combat the COVID-19 virus, are most effective when their mRNA remains stable for an extended period, allowing cells to continually produce proteins that prime the immune system. Conversely, mRNAs involved in creating editing proteins, such as those employed in CRISPR technology for correcting genetic anomalies, necessitate rapid degradation to prevent potential damage to healthy DNA.
Although the CCR4-NOT molecular complex has long been recognized as a key player in mRNA degradation, the mechanisms through which it is specifically recruited to target mRNAs in human cells have remained largely obscure. To address this knowledge gap, researchers from the Mendell Lab and the Erzberger Lab collaborated, each bringing complementary expertise in RNA biology to the investigation. By pooling their resources, the teams focused on identifying human cell mRNAs that exhibited a strong association with the CCR4-NOT complex.
“We found that these mRNAs were highly enriched for the instructions, or codons, that tell the cell to add the amino acid arginine to the encoded protein,” remarked Dr. Erzberger, emphasizing the specificity of their findings.
Intriguingly, the research highlighted that mRNAs responsible for encoding proteins integral to mitochondrial function – the energy-producing organelles of the cell – exhibited the highest correlation with the arginine codons promoting degradation. This discovery led to the insight that impairing the recruitment of CCR4-NOT by tRNAs that recognize arginine codons results in an increase in the abundance and activity of mitochondria within the affected cells, potentially enhancing cellular energy output.
Because mitochondrial mRNAs were most significantly influenced by this newly characterized degradation signal, Dr. Mendell speculated that this mechanism could eventually be harnessed to develop treatments for specific inherited mitochondrial disorders and other diseases where mitochondrial function is compromised, such as obesity and cancer.
Dr. Mendell holds the esteemed Charles Cameron Sprague, M.D. Chair in Medical Science and is a respected member of the Harold C. Simmons Comprehensive Cancer Center, further underscoring the significance of his contributions to medical research.
This innovative research was made possible through generous grants from various esteemed institutions, including the National Institutes of Health (R01CA282036 and GM135617-01), the Cancer Prevention and Research Institute of Texas (CPRIT) (RP220309, RR150074, and RP170644), The Welch Foundation (I-1961 and I-1897), and support from the UTSW Endowed Scholars Fund. The UT Southwestern Cryo-Electron Microscopy Facility is notably supported by grant RP220582 from CPRIT, emphasizing the collaborative effort behind this significant work.
About UT Southwestern Medical Center
UT Southwestern, celebrated as one of the premier academic medical centers in the United States, seamlessly integrates groundbreaking biomedical research with top-tier clinical care and education. The institution boasts faculty members who have collectively earned six Nobel Prizes and includes 25 members of the National Academy of Sciences, 24 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. With a dedicated full-time faculty of over 3,200, UT Southwestern is at the forefront of transformative medical advancements and is committed to expeditiously translating research discoveries into clinical applications. Annually, UT Southwestern physicians deliver exceptional care across more than 80 specialties, managing over 120,000 hospitalized patients, responding to more than 360,000 emergency room cases, and overseeing nearly 5 million outpatient visits.
What role do transfer RNAs play in mRNA stability and how might this understanding influence therapeutic strategies for diseases like obesity and cancer?
**Interview with Dr. Joshua T. Mendell, M.D., Ph.D.**
**Interviewer:** Welcome, Dr. Mendell! Thank you for joining us today to discuss your groundbreaking research published in *Science*. Your findings shed light on the crucial role of transfer RNAs in regulating the stability of messenger RNAs. Can you explain why this discovery is significant?
**Dr. Mendell:** Thank you for having me! Our study highlights a previously underappreciated aspect of transfer RNAs (tRNAs) — their role not just in translating genetic information into proteins, but also in controlling how long messenger RNAs (mRNAs) persist in the cell. The stability of mRNA directly influences protein synthesis levels, which are vital for numerous cellular functions. This connection between tRNAs and mRNA decay could open new avenues for therapeutic strategies targeting diseases like obesity and cancer.
**Interviewer:** Fascinating! You mentioned that specific codons related to the amino acid arginine were linked to mRNA degradation. Can you elaborate on this finding and its implications?
**Dr. Mendell:** Certainly! We discovered that mRNAs associated with the CCR4-NOT complex—the main player in mRNA degradation—were enriched with codons that signal the addition of arginine to proteins. This specificity suggests that the mechanism we uncovered may be finely tuned to regulate the longevity of certain mRNAs. Interestingly, we found that mRNAs encoding proteins critical for mitochondrial function showed the strongest correlation with these arginine codons. This insight points to a potential way of modulating mitochondrial energy production by influencing the decay of these mRNAs.
**Interviewer:** That sounds promising! Could you share how this research may impact treatments for diseases that affect mitochondrial function?
**Dr. Mendell:** Our findings suggest that by understanding how tRNAs interact with mRNAs and the CCR4-NOT complex, we might be able to develop interventions to either stabilize or promote the degradation of specific mRNAs. For conditions like inherited mitochondrial disorders or other diseases where mitochondrial function is compromised, such as obesity and cancer, harnessing this mechanism could lead to innovative therapies that restore or enhance cellular energy output.
**Interviewer:** It’s incredible how fundamental research can lead to potential applications in medicine. What are the next steps for your research team?
**Dr. Mendell:** We plan to further investigate the molecular mechanisms at play between tRNAs, mRNAs, and the CCR4-NOT complex. By dissecting these interactions in various biological contexts, we can gain deeper insights into how mRNA stability affects cellular functions and disease progression. Our goal is to translate this knowledge into practical therapeutic strategies that could one day benefit patients.
**Interviewer:** Thank you, Dr. Mendell, for sharing your insights and highlighting the importance of your research. We look forward to seeing how these findings develop further!
**Dr. Mendell:** Thank you for having me! I’m excited about the possibilities ahead.