Affiliation:
1. Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
2. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Abstract
Hypoxia is important in a wide range of biological processes, such as animal hibernation and cell survival, and is particularly relevant in many diseases. The sensitivity of cells and organisms to hypoxic injury varies widely, but the molecular basis for this variation is incompletely understood. Using forward genetic screens in
Caenorhabditis elegans
, we isolated a hypoxia-resistant reduction-of-function mutant of
rrt-1
that encodes an arginyl–transfer RNA (tRNA) synthetase, an enzyme essential for protein translation. Knockdown of
rrt-1
, and of most other genes encoding aminoacyl-tRNA synthetases, rescued animals from hypoxia-induced death, and the level of hypoxia resistance was inversely correlated with translation rate. The unfolded protein response was induced by hypoxia and was required for the hypoxia resistance of the reduction-of-function mutant of
rrt-1
. Thus, translational suppression produces hypoxia resistance, in part by reducing unfolded protein toxicity.
Publisher
American Association for the Advancement of Science (AAAS)
Cited by
93 articles.
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