Survival from Hypoxia in C. elegans by Inactivation of Aminoacyl-tRNA Synthetases
Lori L. Anderson,1
Xianrong Mao,1
Barbara A. Scott,1
C. Michael Crowder1,2*
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.
2 Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
* To whom correspondence should be addressed. E-mail: crowderm{at}morpheus.wustl.edu
