If a cell is stressed, such as by being exposed to harmful chemicals, it makes fewer proteins in order to conserve its resources. The section of an mRNA molecule before the start codon is not normally translated by the ribosome and is hence called the 5′ untranslated region.īuilding proteins requires energy and resources, and so it is carefully regulated. This step involves identifying an instruction called the start codon that marks the beginning of the mRNA's coding sequence. The first step in the translation process is called ‘initiation’ and requires a protein called eIF2 to work together with the ribosome. These instructions are copied to make a molecule of mRNA, and a molecular machine known as a ribosome then reads and translates the mRNA to build the protein. Proteins carry out essential tasks for living cells and genes contain the instructions to make proteins within their DNA. Phylogenetic analysis suggests that at least two regulatory uORFs (namely, in SLC35A4 and MIEF1) encode functional protein products. Site-specific mutagenesis of two identified stress resistant mRNAs (PPP1R15B and IFRD1) demonstrated that a single uORF is sufficient for eIF2-mediated translation control in both cases. Nearly all resistant transcripts possess at least one efficiently translated upstream open reading frame (uORF) that represses translation of the main coding ORF under normal conditions. Although this led to a 5.4-fold general translational repression, the protein coding open reading frames (ORFs) of certain individual mRNAs exhibited resistance to the inhibition. We carried out ribosome profiling of cultured human cells under conditions of severe stress induced with sodium arsenite. However, the persistent translation of certain mRNAs is required for deployment of an adequate stress response. This can be achieved by the phosphorylation-mediated inactivation of a key translation initiation factor, eukaryotic initiation factor 2 (eIF2). Eukaryotic cells rapidly reduce protein synthesis in response to various stress conditions.
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