Translational adaptation to heat stress is mediated by RNA 5‐methylcytosine in Caenorhabditis elegans. (7th December 2020)

• Record Type: Journal Article
• Authors: Navarro, Isabela Cunha; Tuorto, Francesca; Jordan, David; Legrand, Carine; Price, Jonathan; Braukmann, Fabian; Hendrick, Alan G; Akay, Alper; Kotter, Annika; Helm, Mark; Lyko, Frank; Miska, Eric A
• Is Part Of: EMBO journal. Volume 40:Number 6(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: 5‐methylcytosine -- Caenorhabditis elegans -- NSUN -- RNA modifications -- translation efficiency; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2020105496
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Methylation of carbon‐5 of cytosines (m 5 C) is a post‐transcriptional nucleotide modification of RNA found in all kingdoms of life. While individual m 5 C‐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 5 C in RNA, demonstrating that this modification is non‐essential. Using this genetic tool, we determine the localisation and enzymatic specificity of m 5 C 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 5 C impacts the decoding of some triplets of these two amino acids, leading to reduced translation efficiency. Upon heat stress, m 5 C loss leads to ribosome stalling at UUG triplets, the only codon translated by an m 5 C34‐modified tRNA. This leads to reduced translation efficiency of UUG‐rich transcripts and impaired fertility, suggesting a role of m 5 C tRNA wobble methylation in the adaptation to higher temperatures. SYNOPSIS: Cytosines carbon‐5 methylation (m 5 C) is a conserved RNA modification affected in various diseases, yet its functions and molecular interactions are not well characterized. A mutant C. elegans strain devoid of m 5 C RNA modification reveals its contribution to physiological translation and importance for translational adaptation to heat stress. m 5 C and its derivatives are non‐essential RNA modifications in Caenorhabditis elegans . m 5 C is reliably detected in tRNA, rRNA, and some small non‐coding RNAs, but not in coding transcripts in the nematode. NSUN‐4 acts as a dual rRNA and tRNA methyltransferase in C. elegans mitochondria. m 5 C controls translational efficiency of leucine and proline codons. m 5 C loss reduces C. elegans fertility and Leu‐UUG decoding at elevated temperatures. Abstract : Analysis of worm mutants devoid of m 5 C RNA modifications uncovers their contribution to efficient Leu/Pro codon translation, and requirement for fertility‐supporting Leu‐UUG decoding at higher temperatures.