Selective tRNA charging defects reshape ribosomal pausing and stress adaptation

In wild-type HEK293T and eIF2-S52A cells, halofuginone, histidinol, and Leu-AMS each lowered cognate charged-tRNA pools and increased ribosome occupancy at cognate codons, with codon-specific differences.

• Why it matters: Distinct aminoacyl-tRNA synthetase defects can produce varied disease phenotypes, but it is unclear how selective tRNA charging reshapes codon pausing and stress adaptation in cells.
• What they did: The study combined tRNA charging and abundance measurements with ribosome profiling, RNA sequencing, and proteomics in HEK293T and phosphorylation-deficient eIF2-S52A cells treated with halofuginone, histidinol, or Leu-AMS.
• The result: Ribosomal pausing rose as charged-tRNA availability fell, but Pro and Leu charging decreased more strongly in eIF2-S52A while His charging was better preserved; translational and transcriptional integrated stress response signals were attenuated, yet halofuginone still caused extensive mRNA and ribosome-footprint changes.

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