️ Episode 164: m6A in the coding sequence: linking deposition, translation, and decay

In this episode of PaperCast Base by Base, we explore how N6-methyladenosine (m6A) marks within coding sequences orchestrate a fast, translation-coupled route to mRNA decay, and how splicing- and chromatin-linked mechanisms shape where those marks are placed across transcripts.

Study Highlights:
The authors synthesize recent mapping and mechanistic studies to show that exon-junction complexes restrict METTL3 activity in coding regions, helping define the mature m6A landscape. They describe CDS–m6A decay (CMD), a translation-dependent pathway in which m6A within A-site codons slows decoding, triggers ribosome pausing and collisions, and accelerates selective mRNA degradation. They integrate evidence that CMD targets are enriched in P-bodies and may interface with decapping machinery, while also noting that reader proteins such as YTHDFs and tRNA modifications like mcm5s2U modulate the strength of pausing and decay. They further discuss how deposition timing spans co- and post-transcriptional windows, with transcription dynamics, histone marks, and nuclear retention fine-tuning site selection and stoichiometry. Finally, they highlight physiological links, including regulation of developmentally important transcripts and potential relevance to cancer biology and METTL3-targeted therapeutics.

Conclusion:
CDS-localized m6A acts as a precise switch that couples translation dynamics to rapid mRNA turnover, offering new levers to tune gene expression and potential therapeutic entry points in disease.

Reference:
Ćorović M, Hoch-Kraft P, Zhou Y, Hallstein S, König J, Zarnack K (2025). m6A in the coding sequence: linking deposition, translation, and decay. Trends in Genetics. https://doi.org/10.1016/j.tig.2025.06.002

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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