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: Decoding of messenger RNA (mRNA) occurs during translation, the vital cellular process that builds proteins. Errors in this process are known to lead to cancer growth.
Jude Children's Research Hospital identified how one factor involved in mRNA decoding can be altered, identifying potential cancer origins and new targets for KRAS-related treatment resistance. The results are published in Nature Cell Biology. To add the correct building block to a protein, the ribosome (the molecular machine that makes proteins) reads codons (a grouping of three nucleotides) in a process called mRNA decoding during translation elongation.
The translation elongation factor eEF1A influences the speed and accuracy of mRNA decoding. It was known that, in certain tumors, the METTL13 enzyme modifies eEF1A at lysine 55 (eEF1AK55me2), thus increasing protein synthesis and promoting tumor growth. How eEF1AK55me2 affects translation elongation and contributes to tumor growth was unknown.
"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, Ph.D., 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." The work built upon findings from a study the St.
Jude team published in Nature in 2023, in which they used cryo-electron microscopy to determine the atomic structure of human ribosomes bound to eEF1A and compared mRNA decoding in human and bacterial translation. That study created a foundation to examine the effect of the eEF1AK55me2-METTL13 axis on translation. Through proteomic profiling and single-molecule imaging, the team found that the axis promotes efficient translation of a subset of codons that are enriched in oncogenes, such as KRAS.
Because KRAS is an oncogenic driver present in many tumor types, understanding how it is expressed and how it develops resistance to standard-of-care treatments is of interest to the oncology field. The team further examined METTL13 disruption as a potential target to overcome KRAS-related treatment resistance and observed stymied growth of KRAS-inhibitor–resistant tumors in animal models. These findings have implications for developing future treatment strategies in which METTL13 could be used as a target to inhibit KRAS production in tumors.
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