Ribosomal Biogenesis is a Convergent Regulator of Hypoxic Injury

Besides its primary function in protein synthesis, the translation machinery also controls lifespan and hypoxic cellular injury through unclear mechanisms. In a forward mutagenesis screen in C. elegans for mutations that protect from hypoxic death, we identified a loss-of-function mutation in ddx-52, which encodes an RNA helicase homologous to the yeast small subunit ribosomal maturation protein ROK1. To define the function of ddx-52, we performed a second mutagenesis screen for suppressors of a conditional developmental arrest phenotype of ddx-52(lf). Mutations in multiple genes regulating ribosomal biogenesis were identified as suppressors of both the developmental arrest and hypoxic survival phenotypes of ddx-52(lf), confirming the function of DDX-52 in ribosomal maturation. Two ddx-52(lf) suppressor genes, larp-1 and ncl-1, that control ribosomal protein translation and ribosomal RNA synthesis, respectively, were tested for suppression for additional hypoxia resistant mutant genes isolated in the initial screen and known to function in translation. Surprisingly, the larp-1 and ncl-1 mutations likewise suppressed the hypoxia resistance of mutations in genes functioning in tRNA biogenesis but did not alter the hypoxia resistance of a peptide transporter known to promote translation. Direct measurement of protein synthesis showed that restoration of translation rates was necessary for the suppression of hypoxia resistance. larp-1 and ncl-1 serve as convergent regulators of hypoxia injury by coordinating tRNA metabolism with ribosomal biogenesis.