Scientists at St. Jude Children’s Research Hospital have uncovered how a mechanism controlling messenger RNA (mRNA) decoding can contribute to cancer development and treatment resistance. The findings, published in Nature Cell Biology, reveal how the enzyme METTL13 modifies a protein involved in protein synthesis, potentially opening new avenues for targeting cancers driven by KRAS.
During translation, ribosomes read mRNA sequences to assemble proteins. They interpret codons, groups of three nucleotides that specify amino acids, through a process known as mRNA decoding. The elongation factor eEF1A helps regulate the speed and accuracy of this process.
Previous research established that METTL13 can modify eEF1A at a specific location, lysine 55. This modification, known as eEF1AK55me2, increases protein synthesis and supports tumour growth in certain cancers. However, scientists did not fully understand how this modification affected translation or contributed to cancer development.
To investigate, researchers created cell lines lacking METTL13 and compared eEF1A with and without the enzyme-mediated modification. They then used parallel single-molecule imaging to examine how the modification influenced mRNA decoding.
“We worked collaboratively with our co-authors to create cell lines that lacked METTL13 to recombinantly express eEF1 with and without METTL13-mediated methylation,” said co-corresponding author Scott Blanchard, from the St. Jude Department of Structural Biology. “We then leveraged the power of parallelized single-molecule imaging experiments to demonstrate that eEF1AK55me2 affects mRNA decoding in a way that rationalized our collaborators’ observations in quantitative, kinetic and structural terms.”
METTL13 May Offer a Target Against KRAS-Driven Cancers
Building on a 2023 study that examined human ribosomes using cryo-electron microscopy, the researchers combined proteomic profiling with single-molecule imaging to investigate the relationship between METTL13, eEF1A and translation.
They discovered that this molecular pathway promotes the efficient translation of certain codons that occur frequently in oncogenes, including KRAS. Because KRAS drives the development of numerous cancer types, understanding how cells produce this protein could help researchers address resistance to existing treatments.
The team investigated whether disrupting METTL13 could help overcome resistance to KRAS inhibitors. In animal models, interfering with METTL13 slowed the growth of tumours that had become resistant to KRAS-targeted treatment.
The researchers also found that eliminating METTL13 did not cause toxic effects in healthy preclinical models, an encouraging observation for potential therapeutic development. However, further research would be necessary to establish whether targeting the enzyme is safe and effective in humans.
“Our team’s research demonstrates that this methyltransferase stimulates the translation of KRAS and other proliferation-promoting proteins. Reducing KRAS production, a known driver of many cancers, can be achieved by knocking down METTL13 using a drug or some other mechanism, so that KRAS-driven cancer patients can have a better chance of survival,” Blanchard said.
Changes in Translation Speed Affect Protein Production
The study also revealed that translation elongation does not occur at a uniform rate. Even codons that encode the same amino acid can be decoded at different speeds depending on whether eEF1A has been methylated at lysine 55.
“There is a growing understanding that protein synthesis occurs at rates that are not uniform. In our findings, we showed that even two related codons, encoding the same amino acid but differing in the third nucleotide position, can show different decoding speeds in a manner that depends on eEF1A K55 methylation,” Blanchard said. “When METTL13 is present and eEF1A K55 is methylated, the two related codons are decoded at very similar rates; when METTL13 is absent, the codons are decoded at different rates.”
METTL13 Activity Could Help Predict Cancer Outcomes
Researchers also investigated whether METTL13 activity was associated with patient outcomes. They compared preclinical findings with clinical outcome data from patients with lung adenocarcinoma and pancreatic ductal adenocarcinoma, two cancer types in which METTL13 is frequently amplified.
Their analysis found that increased methyltransferase activity correlated with poorer prognosis, suggesting that METTL13 could potentially help identify more aggressive cancers.
“We found that you can look for the activity of this methyltransferase in cancer, because high activity of METTL13 seems to correlate with aggressive cancer and lower survival,” said co-first author Aaron Cruz-Navarrete of the St. Jude Department of Structural Biology. “Our results show there’s a potential to use the activity of this methyltransferase as a prognostic tool.”
Read More :