Abstract
Reactive oxygen species (ROS) are toxic by-products of normal aerobic metabolism. ROS can damage mRNAs and the translational apparatus resulting in translational defects and aberrant protein production. Three mRNA quality control systems monitor mRNAs for translational errors: nonsense-mediated decay, non-stop decay (NSD) and no-go decay (NGD) pathways. Here, we show that factors required for the recognition of NSD substrates and components of the SKI complex are required for oxidant tolerance. We found an overlapping requirement for Ski7, which bridges the interaction between the SKI complex and the exosome, and NGD components (Dom34/Hbs1) which have been shown to function in both NSD and NGD. We show that ski7 dom34 and ski7 hbs1 mutants are sensitive to hydrogen peroxide stress and accumulate an NSD substrate. We further show that NSD substrates are generated during ROS exposure as a result of aggregation of the Sup35 translation termination factor, which increases stop codon read-through allowing ribosomes to translate into the 3΄-end of mRNAs. Overexpression of Sup35 decreases stop codon read-through and rescues oxidant tolerance consistent with this model. Our data reveal an unanticipated requirement for the NSD pathway during oxidative stress conditions which prevents the production of aberrant proteins from NSD mRNAs.
Highlights
Reactive oxygen species (ROS) are ubiquitous molecules formed as a by-product of aerobic metabolism and following exposure to diverse radical-generating compounds
We found that mutants lacking UPF1, UPF2, DOM34 or HBS1 were unaffected in H2O2 sensitivity, suggesting that nonsense-mediated decay (NMD) and no-go decay (NGD) are not required for oxidant tolerance (Figure 1A)
To confirm the difference in H2O2 sensitivity between the ski7 and ski8 mutants, we examined whether the loss of SKI7 or SKI8 alters growth kinetics during oxidative stress conditions
Summary
Reactive oxygen species (ROS) are ubiquitous molecules formed as a by-product of aerobic metabolism and following exposure to diverse radical-generating compounds. ROS are well known toxicants which damage cellular macromolecules and have been implicated in the cause and progression of many disease processes including cancer, neurodegenerative and cardiovascular diseases [1]. To protect against such oxidative damage, cells contain effective defense mechanisms including antioxidant enzymes and free radical scavengers. Despite these protective systems, an oxidative stress occurs when there is an imbalance between radical production and stress protection. Such oxidative stress can result in oxidative damage to most cellular macromolecules and this damage has been implicated in aging and cell death
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