Ribosomal and tRNA Biogenesis Interact to Control Hypoxic Injury and Translation

Protein translation is an essential cellular process, but paradoxically, it can also promote aging and other stresses. In a screen for mutations that protect C. elegans from hypoxic stress, we isolated multiple genes that impact translation, including a ribosomal RNA helicase gene, ddx-52, tRNA biosynthesis genes, and a gene controlling amino acid availability. To better define the mechanisms whereby these genes control hypoxic injury, we performed a second screen for genetic suppressors of the ddx-52(lf) phenotypes. This screen identified multiple genes involved in ribosome biogenesis. Surprisingly, the suppressor mutations were able to restore normal hypoxic sensitivity and protein synthesis to the tRNA biosynthesis mutants, but not to the mutant reducing amino acid uptake. Proteomic characterization of the mutants demonstrated that reduced tRNA biosynthetic activity produces a corresponding reduction in ribosomal structural subunits. Our study uncovers an uncharacterized regulatory interaction between ribosomal biogenesis and tRNA abundance controlling translation and hypoxic survival. A proteomic analysis of a threonyl-tRNA synthetase mutant with and without the ribosomal biogenesis suppressors revealed an uncharacterized feedback mechanism whereby disruption of tRNA aminoacylation results in a corresponding reduction in ribosomal subunits, thereby explaining the ability of enhanced ribosomal biogenesis to suppress reduced tRNA aminoacylation.