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| Title | Suboptimal codon pairs trigger ribosome collisions and cellular quality control responses in tRNA modification mutants. |
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| Journal, issue, pages | Nucleic Acids Res, Vol. 53, Issue 22, Year 2025 |
| Publish date | Nov 26, 2025 |
 Authors | Jie Wu / Cristian Eggers / Olga Sin / Łukasz Koziej / Hector Mancilla / Fabienne Mollet / Hans R Schöler / Hannes C A Drexler / Tristan Ranff / Christian Fufezan / Claudine Kraft / Sebastian Glatt / Jan M Bruder / Sebastian A Leidel /     |
| PubMed Abstract | Transfer RNA (tRNA) modifications tune translation rates and codon optimality, thereby optimizing co-translational protein folding. However, the mechanisms by which tRNA modifications modulate codon ...Transfer RNA (tRNA) modifications tune translation rates and codon optimality, thereby optimizing co-translational protein folding. However, the mechanisms by which tRNA modifications modulate codon optimality and trigger phenotypes remain unclear. Here, we show that ribosomes stall at specific modification-dependent codon pairs in wobble uridine modification (U34) mutants. This triggers ribosome collisions and a coordinated hierarchical response of cellular quality control pathways. High-resolution ribosome profiling reveals an unexpected functional diversity of U34 modifications during decoding. For instance, 5-carbamoylmethyluridine (ncm5U) exhibits distinct effects at the A and P sites. Importantly, ribosomes only slow down at a fraction of codons decoded by hypomodified tRNA, and the decoding speed of most codons remains unaffected. However, the translation speed of a codon largely depends on the identity of A- and P-site codons. Stalling at modification-dependent codon pairs induces ribosome collisions, triggering ribosome-associated quality control (RQC) and preventing protein aggregation by degrading aberrant nascent peptides and messenger RNAs. Inactivation of RQC stimulates the expression of molecular chaperones that remove protein aggregates. Our results demonstrate that loss of tRNA modifications primarily disrupts translation rates of suboptimal codon pairs, showing the coordinated regulation and adaptability of cellular surveillance systems. These systems ensure efficient and accurate protein synthesis and maintain protein homeostasis. |
 External links | Nucleic Acids Res / PubMed:41429421 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 1.81 - 3.0 Å |
| Structure data |  EMDB-19945: Yeast 80S ribosome (ncs2 elp6 -/-) PRE-translocation-hybrid P/E A/A* (PRE-H2) dataset 1/2  EMDB-19946: Yeast 80S ribosome (ncs2 elp6 -/-) PRE-translocation-hybrid P/E A/A* (PRE-H2) dataset 2/2  EMDB-19947: Yeast 80S ribosome (wild type) PRE-translocation-hybrid P/E A/A* (PRE-H2) dataset 1/2  EMDB-19948: Yeast 80S ribosome (wild type) PRE-translocation-hybrid P/E A/A* (PRE-H2) dataset 2/2  EMDB-19949: Yeast 80S ribosome PRE-translocation-hybrid P/E A/A (PRE-H1)  EMDB-19950: Yeast 80S ribosome posttranslocation non-rotated P/P (POST2-NR)  EMDB-19951: Yeast 80S ribosome PRE-translocation non-rotated P/P A/A (PRE-NR)  EMDB-19952: Yeast 80S ribosome posttranslocation non-rotated E/E P/P (POST1-NR)  EMDB-19953: Yeast 80S ribosome splitting complex with P/P tRNA, eRF1, and ABCE1 (SC) |
| Source |
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Saccharomyces cerevisiae (brewer's yeast)