Translational adaptation to heat stress is mediated by RNA 5‐methylcytosine in Caenorhabditis elegans

Isabela Cunha Navarro, Francesca Tuorto, David Jordan, Carine Legrand, Jonathan Price, Fabian Braukmann, Alan G. Hendrick, Alper Akay, Annika Kotter, Mark Helm, Frank Lyko, Eric A. Miska

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Methylation of carbon-5 of cytosines (m 5C) is a post-transcriptional nucleotide modification of RNA found in all kingdoms of life. While individual m 5C-methyltransferases have been studied, the impact of the global cytosine-5 methylome on development, homeostasis and stress remains unknown. Here, using Caenorhabditis elegans, we generated the first organism devoid of m 5C in RNA, demonstrating that this modification is non-essential. Using this genetic tool, we determine the localisation and enzymatic specificity of m 5C sites in the RNome in vivo. We find that NSUN-4 acts as a dual rRNA and tRNA methyltransferase in C. elegans mitochondria. In agreement with leucine and proline being the most frequently methylated tRNA isoacceptors, loss of m 5C impacts the decoding of some triplets of these two amino acids, leading to reduced translation efficiency. Upon heat stress, m 5C loss leads to ribosome stalling at UUG triplets, the only codon translated by an m 5C34-modified tRNA. This leads to reduced translation efficiency of UUG-rich transcripts and impaired fertility, suggesting a role of m 5C tRNA wobble methylation in the adaptation to higher temperatures.

Original languageEnglish
Article numbere105496
JournalThe EMBO Journal
Issue number6
Early online date7 Dec 2020
Publication statusPublished - 15 Mar 2021


  • 5-methylcytosine
  • Caenorhabditis elegans
  • NSUN
  • RNA modifications
  • translation efficiency

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