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.