Oral Presentation Australasian RNA Biology and Biotechnology Association 2025 Conference

tRNA modifications tune m6A-dependent mRNA decay (128033)

Linder Bastian 1 , Puneet Sharma 2 , Jie Wu 2 3 , Tosca Birbaumer 2 , Cristian Eggers 2 , Shino Murakami 4 , Kai Fenzl 1 , Hannah Vorgerd 5 , Florian Erhard 6 , Jaffrey Samie 4 , Sebastian A Leidel 2 7 , Lars Steinmetz 1 3
  1. Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
  2. University of Bern, Bern, BERN, Switzerland
  3. Stanford Genome Technology Center, Stanford University, Palo Alto, California, USA
  4. Department of Pharmacology, Cornell University, New York, USA
  5. RNA Biology group, Max-Planck-Institute for Molecular Biomedicine, Muenster, Germany
  6. Chair of Computational Immunology, University of Regensburg, Regensburg, Germany
  7. RNA Biology Group, Max-Planck-Institute for Molecular Biomedicine, Muenster, Germany

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 novel mechanism by which the epitranscriptomic mark N6-methyladenosine (m6A) couples mRNA translation to decay. m6A-modified codons are decoded inefficiently by the ribosome, rendering them “non-optimal” and inducing ribosome collisions on cellular transcripts. This triggers translation-dependent mRNA decay. The modified nucleotide 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U) in the tRNA anticodon improves the decoding of m6A-modified codons and counteracts m6A-driven mRNA decay. 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 towards more mcm5s2U - is associated with more aggressive tumors and poor prognosis. Overall, this panepitranscriptomic interaction represents a novel mechanism of post-transcriptional gene regulation with implications for human health.