A protein that regulates mRNA decoding can itself be regulated with implications for understanding cancer

Within the realm of cellular processes, the accurate translation of messenger RNA (mRNA) into proteins is paramount. Errors in this procedure have been linked to the development of cancer. Researchers at St. Jude Children's Research Hospital have recently discovered a potential pathway through which one component involved in mRNA decoding can be manipulated, thereby unveiling new treatment avenues for KRAS-related resistance. Their findings have been published in Nature Cell Biology.

During protein synthesis, the ribosome, the cellular machinery responsible for protein creation, reads codons—groups of three nucleotides—in a process termed mRNA decoding during translation elongation. The translation elongation factor eEF1A plays a crucial role in dictating the pace and precision of mRNA decoding. Previous research has established that in certain tumors, the METTL13 enzyme modifies eEF1A at lysine 55 (eEF1AK55me2), thus accelerating protein synthesis and fueling tumor growth.

However, the precise mechanisms by which eEF1AK55me2 influences translation elongation and its contribution to tumor growth remained unclear.

In pursuit of answers, scientists collaborated to develop cell lines devoid of METTL13, which were then engineered to express either eEF1A with or without the METTL13-induced methylation. Utilizing parallelized single-molecule imaging experiments, the team elucidated that eEF1AK55me2 exerts an impact on mRNA decoding, aligning with the collaborators' earlier observations in terms of quantitative, kinetic, and structural data.

Building on earlier research from 2023, where St. Jude researchers utilized cryo-electron microscopy to determine the atomic structure of human ribosomes bound to eEF1A and contrasted mRNA decoding between human and bacterial translation, the current study aimed to explore the implications of the eEF1AK55me2-METTL13 axis on translation.

Through proteomic profiling and single-molecule imaging, they discovered that this axis fosters efficient translation of a particular subset of codons that are overrepresented in oncogenes, such as KRAS. KRAS is an oncogenic protein prevalent in numerous tumor types, making it a focal point for oncology research.

Further investigation into METTL13 disruption as a potential therapeutic target revealed promising results in animal models. Disrupting METTL13 led to a slowdown in the growth of KRAS-inhibitor-resistant tumors. These results suggest that targeting METTL13 could serve as a strategy to counteract KRAS-related treatment resistance, potentially paving the way for new therapeutic approaches.

In healthy preclinical models, the absence of METTL13 did not result in any adverse effects, indicating a favorable safety profile for potential clinical applications. The research team observed that knocking out METTL13 did not cause toxic outcomes, which is a significant advantage for developing drugs targeting this enzyme.

Notably, the study also uncovered that the speed at which eEF1A K55 is methylated varies, significantly impacting protein production. When METTL13 is absent, codons encoding the same amino acid but differing in the third nucleotide position are decoded at different rates. This variability in translation speed has implications for understanding the heterogeneous nature of protein synthesis.

The researchers further examined the correlation between METTL13 activity and cancer prognosis. In preclinical models, the disruption of METTL13 prevented tumor growth, while outcomes from patients with lung adenocarcinoma and pancreatic ductal adenocarcinoma, two cancers in which METTL13 is often overexpressed, indicated that higher METTL13 activity was associated with poorer prognosis. These findings suggest that monitoring METTL13 activity could serve as a prognostic tool in cancer diagnosis and treatment planning.

In conclusion, the St. Jude research team has demonstrated that METTL13 methylation of eEF1A at lysine 55 enhances the decoding of codons enriched in KRAS and other oncogenes, thereby shaping cancer proteomes. By disrupting METTL13, they observed a suppression of KRAS-inhibitor-resistant tumor growth in animal models, without observing any toxicity in healthy preclinical models.

Additionally, the study highlights a potential link between METTL13 activity and patient outcomes in certain cancers, opening up new possibilities for using METTL13 level as a prognostic indicator.