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The cell stress response: extreme times call for post‐transcriptional measures

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Abstract Following cell stress, a wide range of molecular pathways are initiated to orchestrate the stress response and enable adaptation to an environmental or intracellular perturbation. The post‐transcriptional regulation strategies adopted during the stress response result in a substantial reorganization of gene expression, designed to prepare the cell for either acclimatization or programmed death, depending on the nature and intensity of the stress. Fundamental to the stress response is a rapid repression of global protein synthesis, commonly mediated by phosphorylation of translation initiation factor eIF2α. Recent structural and biochemical information have added unprecedented detail to our understanding of the molecular mechanisms underlying this regulation. During protein synthesis inhibition, the translation of stress‐specific mRNAs is nonetheless enhanced, often through the interaction between RNA‐binding proteins and specific RNA regulatory elements. Recent studies investigating the unfolded protein response (UPR) provide some important insights into how posttranscriptional events are spatially and temporally fine‐tuned in order to elicit the most appropriate response and to coordinate the transition from an early, acute stage into the chronic state of adaptation. Importantly, cancer cells are known to hi‐jack adaptive stress response pathways, particularly the UPR, to survive and proliferate in the unfavorable tumor environment. In this review, we consider the implications of recent research into stress‐dependent post‐transcriptional regulation and make the case for the exploration of the stress response as a strategy to identify novel targets in the development of cancer therapies. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution Translation > Translation Mechanisms > Translation Regulation
Summary of posttranscriptional regulation strategies during the stress response. (a) Regulation of ternary complex formation through phosphorylation of eIF2α. eIF2 is an heterotrimer consisting of subunits α, β, and γ. Subunit γ contains the binding sites for GDP/GTP. During the integrated stress response (ISR), phosphorylation of the regulatory subunit α results in impaired formation of the ternary complex and consequent inhibition of protein synthesis. (b) Regulation of eIF4F complex formation through 4E‐BPs. In unstressed conditions, 4E‐BPs are present in their mTOR‐mediated phosphorylated form, unable to bind 4E that can then engage in the formation of the eIF4F complex. During stress, unphosphorylated 4E‐BPs sequester eIF4E away from 4F formation, thus impairing translation initiation. (c) Translation elongation is regulated through phosphorylation of eEF2, mediated by eEF2K, which is in turn negatively regulated by mTOR in unstressed conditions and activated upon stress. (d) Formation of stress granule is triggered upon translation inhibition. (e) Several 5′ UTR regulatory elements can affect translation. (f) tRNAs are targets of translation regulation through modulation of their abundance, modification, and fragmentation. [Correction added on 10 December 2019 after first online publication: Figure 1 has been updated.]
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Schematic representation of GO annotation of cancer fitness genes and RBPs. (a) Number of cancer fitness genes (left box, data from Behan et al., ) and RBPs (right box, data from Queiroz et al., ; Trendel et al., ) annotated with GO terms for UPR (purple), starvation (red), and hypoxia (yellow/orange). The overlap between Venn diagrams indicates the number of genes listed as both cancer fitness genes and RBPs, annotated with each of the GO terms mentioned above. (b) Heatmap showing a subset of cancer fitness genes involved in the UPR (y axis, n = 21 for GO:0030968) and their importance across cancer types (x axis). Red = important for cancer fitness; white = not important for cancer fitness. GO, gene ontology; RBPs, RNA‐binding proteins
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Summary of the unfolded protein response. During ER stress, the three branches of the UPR (ATF6, IRE1, and PERK) are activated through ER chaperone BiP. PERK phosphorylates eIF2α, causing translation inhibition and translation of stress‐specific transcripts. IRE1 splices XBP1 mRNA to obtain functional transcription factor XBP1. ATF6 is relocated to the Golgi, where it is cleaved. XBP1 and cleaved ATF6 relocate to the nucleus to enhance the expression of stress‐specific genes. UPR, unfolded protein response
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Summary of the integrated stress response. Following different stress stimuli, the eIF2α kinases are activated via autophosphorylation and dimerisation. The kinases subsequently phosphorylate eIF2α, which will sequester eIF2B thus leading to inhibition of protein synthesis, translation of stress‐specific transcripts such as transcription factor ATF4, and stress granule formation
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