We are interested in identifying genes that regulate cellular response to and survival from hypoxia. To that end, we performed a forward ENU genetic screen to identify genes necessary for hypoxic death. We identified six conserved genes; five of these genes (
pept-1,
tars-1,
rtcb-1,
xpo-3 and
ddx-52) are predicted to be necessary for normal global protein synthesis. To understand how alterations in protein synthesis lead to hypoxia resistance, we performed a suppressor screen using a temperature sensitive growth arrest phenotype of
ddx-52(lf). DDX-52 is an RNA helicase involved in ribosome biogenesis. Identified suppressors include genes involved in: repression of translation, desumoylation of proteins and regulators of ribosome biogenesis. In addition to suppressing hypoxia resistance of
ddx-52(lf), mutations in repressors of translation
larp-1 (encodes an RNA binding protein) and
ncl-1 (encodes a B-box zinc finger protein) suppressed the hypoxia resistance of mutants involved in tRNA metabolism (
tars-1,
rtcb-1 and
xpo-3). To determine if
ncl-1(lf) and
larp-1(lf) are regulating translation rate of
tars-1(rf) (encoding threonyl tRNA synthetase) animals, we measured translation rate using SILAC incorporation. While
tars-1(rf) animals had reduced global translation rate compared to wild type and to
larp-1(lf)
ncl-1(lf) animals, the global translation rate of
tars-1(rf);
larp-1(lf)
ncl-1(lf) animals was not different from
tars-1(rf) animals. Thus, translation rate per se does not determine hypoxic sensitivity. We propose that multicellular organisms have evolved mechanisms of sensing and coordinating translation capacity for various physiological functions. These mechanisms may insure the survival of animals exposed to stressors that cause reduced translation. Our data demonstrate the crucial role that translation mechanisms have in hypoxic sensitivity. The translation machinery involves hundreds of genes, but our genetic approach allows us to identify specific factors that serve as regulatory hot spots in the overall control of translation and hypoxic survival.