Show Notes
️ Episode 46: Pan-Epitranscriptomic Control — How tRNA and m6A Interact to Regulate mRNA Decay
In this episode of Base by Base, we delve into a landmark study by Linder et al. (2025), published in Cell, which uncovers a molecular interaction between two layers of RNA modifications — m6A in mRNA and mcm5s2U in tRNA — that tunes mRNA stability in a codon-specific and translation-dependent manner. The authors present a compelling model where tRNA modifications actively influence the functional outcome of m6A deposition, linking codon optimality with mRNA decay and revealing an unexpected coordination between translation and post-transcriptional regulation.
Study Highlights:
The study demonstrates that m6A marks in the coding sequence (CDS) reduce codon optimality, slowing translation and triggering mRNA decay. This effect is particularly strong at specific codons and leads to ribosome collisions, which initiate decay pathways. Importantly, the tRNA modification mcm5s2U counteracts this effect by improving decoding efficiency at these sites, especially for codons like AGA and GAA. Loss of mcm5s2U leads to exaggerated decay of m6A-modified transcripts, revealing a finely tuned epitranscriptomic axis. The researchers also show that many of the affected transcripts belong to oncogenic signaling pathways, and that the balance between m6A and mcm5s2U acts as a pan-cancer biomarker, with increased mcm5s2U linked to tumor aggressiveness and poor prognosis. This interplay offers a novel framework for understanding RNA stability, cancer progression, and potential therapeutic vulnerabilities.
Conclusion:
This work defines a new paradigm in RNA biology — a pan-epitranscriptomic system in which modifications in both mRNA and tRNA converge to control gene expression at the level of mRNA decay. By modulating translation kinetics at the codon level, the cell can fine-tune the lifespan of specific mRNAs, especially those involved in tightly regulated pathways like oncogenesis. These findings not only reshape our understanding of the epitranscriptome but also open avenues for new diagnostic and therapeutic strategies in cancer and beyond.
Reference:
Linder, B., Sharma, P., Wu, J., et al. (2025). tRNA modifications tune m6A-dependent mRNA decay. Cell, 188, 1–13. https://doi.org/10.1016/j.cell.2025.04.013
License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
