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tRNA modifications tune m6A-dependent mRNA decay

Bastian Linder1, Puneet Sharma2, Jie Wu3

  • 1Genome Biology Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany.

Cell
|May 1, 2025
PubMed

Insights

Messenger RNA (mRNA) N6-methyladenosine (m6A) modifications are read by transfer RNAs (tRNAs) during translation, coupling mRNA decay to translation. This epitranscriptomic interaction impacts gene regulation and cancer progression.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Biology

Background:

  • Chemically modified nucleotides in mRNA regulate gene expression via reader proteins.
  • N6-methyladenosine (m6A) is a key epitranscriptomic mark on mRNA.
  • Transfer RNAs (tRNAs) also contain modifications, such as 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U).

Purpose of the Study:

  • To elucidate the mechanism by which m6A on mRNA is read by tRNAs during translation.
  • To investigate the functional consequences of this mRNA-tRNA epitranscriptomic interaction.
  • To explore the role of this mechanism in cancer and its potential as a prognostic marker.

Main Methods:

  • Investigated ribosome dynamics and mRNA decay in response to m6A modification.
  • Analyzed the role of tRNA modification mcm5s2U in counteracting m6A-mediated effects.
  • Examined the association between m6A and mcm5s2U biogenesis pathways and tumor aggressiveness in cancer patients.

Main Results:

  • m6A-modified codons are decoded inefficiently by ribosomes, causing collisions and coupling translation to mRNA decay.
  • The tRNA modification mcm5s2U counteracts the ribosome stalling induced by m6A.
  • A shift towards increased mcm5s2U in cancer is linked to more aggressive tumors and poorer prognosis.

Conclusions:

  • A novel pan-epitranscriptomic mechanism links mRNA m6A and tRNA mcm5s2U to regulate gene expression post-transcriptionally.
  • This interaction enables coordinated decay of mRNA regulons, including those in oncogenic pathways.
  • Dysregulation of these epitranscriptomic pathways has significant implications for human health, particularly in cancer.
Keywords:
N(6)-methyladenosinecancerepitranscriptomem(6)AmRNA decaymRNA translationmcm(5)s(2)Uoncogenic signalingribosome collisionstRNA modification

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