ИСТИНА

Eukaryotic cells rapidly switch off protein synthesis in response to various stress conditions. This can be achieved by the phosphorylation-mediated inactivation of a key translation initiation factor, eIF2. However, the persistent translation of certain mRNAs is thought to be required for deployment of an adequate stress response. We carried out ribosome profiling of cultured human cells under conditions of severe oxidative stress induced with sodium arsenite. We found that despite 4-5 folds general repression, translation of certain individual transcripts is resistant or even induced under stress conditions. These transcripts possess efficiently translated uORFs which repress translation of their main coding ORFs under normal conditions. This repression is relieved upon eIF2 inactivation. We carried out site specific mutagenesis for uORFs of two newly identified stress resistant mRNAs (PPP1R15B and IFRD1) and found that a single uORF translation is required for eIF2- mediated translation control. However, we also observed efficient translation of uORFs in about 11% of those mRNA that are not resistant. Cross-species comparative sequence analysis suggests that in addition to the regulatory role, at least some of these uORFs (namely in SLC35A4 and in MIEF1) encode functional protein products. Analysis of public ribosome profiling data indicates that under most conditions the main products of these mRNAs are encoded by uORF while products of annotated ORFs are specific to stress conditions. Translation of uORFs is vital for mRNAs to resist eIF2 mediated stress response translation, but is insufficient. Some of uORFs in stress resistant mRNAs encode functional protein products.