Modifications Specify a New mRNA Degradation Pathway connected to Cancer

The Leidel and Steinmetz labs discovered that the relative levels of the mRNA modification m6A and the tRNA modification mcm5s2U control the degradation rate of m6A modified mRNAs. Codons bearing the m6A modification lead to a slow down of translation and mRNA degradation. If the mcm5s2U modification is present in the anticodon loop, then the slowdown of translation and mRNA degradation are alleviated. In cancers, increased levels of the tRNA modification mcm5s2U go along with more aggressive tumorous and poorer prognosis, pointing towards a diagnostic application of these findings. This mechanism can regulate functionally related groups of mRNAs, so called mRNA regulons. Also, it explains why even positions which are lowly modified with m6A can have an effect, as the cumulative effect of all m6A sites in the coding region affects the decay of a given mRNA. Their findings have been published in the journal Cell in the article “tRNA modifications tune m6A-dependent mRNA decay”.

Highlights

  • m6A in mRNA deoptimizes specific codons and couples mRNA translation to decay
  • mcm5s2U in tRNA modulates the decoding of m6A-modified codons
  • The mcm5s2U/m6A system tunes the decay of functionally related mRNA regulons
  • The mcm5s2U/m6A system is involved in cancer

Summary
Chemically modified nucleotides in mRNA are critical regulators of gene expression, primarily through interactions with reader proteins that bind to these modifications. Here, we present a mechanism by which the epitranscriptomic mark N6-methyladenosine (m6A) is read by tRNAs during translation. Codons that are modified with m6A are decoded inefficiently by the ribosome, rendering them "non-optimal" and inducing ribosome collisions on cellular transcripts. This couples mRNA translation to decay. 5-Methoxycarbonylmethyl-2-thiouridine (mcm5s2U) in the tRNA anticodon loop counteracts this effect. This unanticipated link between the mRNA and tRNA epitranscriptomes enables the coordinated decay of mRNA regulons, including those encoding oncogenic signaling pathways. In cancer, dysregulation of the m6A and mcm5s2U biogenesis pathways-marked by a shift toward more mcm5s2U-is associated with more aggressive tumors and poor prognosis. Overall, this pan-epitranscriptomic interaction represents a novel mechanism of post-transcriptional gene regulation with implications for human health.

Read the Publication in Cell (Open Access)

Website Leidel Lab

Figure, highlights and summary from Linder, Sharma, Wu et al. (2025) Cell published under a CC BY 4.0 license