The non-stop decay mRNA surveillance pathway is required for oxidative stress tolerance

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.

The No-Go and Nonsense-Mediated RNA Decay Pathways Are Regulated by Inflammatory Cytokines in Insulin-Producing Cells and Human Islets and Determine β-Cell Insulin Biosynthesis and Survival

“…NO-mediated nitration activates the NF-kB (34,35), p53 (36), AP-1 (37), and other signaling pathways (35). Alternatively, nucleotide nitration leading to 8-nitroguanosine modifications of cellular RNAs may cause ribosomal stalling (7,38) and mediate RDPC expressional upregulation as a protective response. Measurement of 8-nitroguanosine modifications in cytokine-exposed INS-1 cells failed due to a lack of specific and sensitive methods (data not shown).…”

“…At least four forms of cotranslational mRNA quality control pathways have been described: nonsense-mediated decay (NMD), Staufen1 (STAU1)-mediated mRNA decay (SMD), no-go decay (NGD), and nonstop decay (NSD) (7)(8)(9). Both NSD and NGD pathways share the ribosomal dissociation factor Pelo, which is necessary for degradation of "non-stop codon" mRNAs and damaged mRNAs that cause translational stalling, respectively (10).…”

The emerging role of RNA modifications in the regulation of mRNA stability

“…The oxidation of mRNA affects multiple steps of mRNA fate determination, including mRNA stability and translation 12,[70][71][72][73] . For instance, the oxidation of mRNA (typically 8-oxoG) inhibits the efficiency of peptide bond formation by >1000-fold, regardless of the codon position 71 .…”

RNA degradation sculpts the maternal transcriptome duringDrosophilaoogenesis

“…However, we did find evidence that no-go decay (NGD), which is activated when ribosomes stall on RNAs, was involved in the degradation of Tst-regulated RNAs. Pelota (Pelo/DOM34) is a critical effector protein of the NGD pathway that promotes recycling of stalled ribosomes on mRNAs 27,48,49 . Intriguingly, pelo mutants, like tst mutants, are homozygous viable but female sterile, and this role is germline specific 50 .…”