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- Regulation of PERK gene expression by its upstream open reading framesPublication . Ponte, João Gonçalves da; Zilhão, Rita; Romão, LuísaUpstream open reading frames (uORFs) are cis-acting elements located within the 5’ untranslated region (5’UTR) of transcripts, which can regulate the translation of the corresponding main open reading frame (mORF). In normal conditions, uORFs are typically repressors of downstream translation, as they can block ribosomal access to the mORF or even induce mRNA degradation through the nonsense-mediated mRNA decay (NMD) pathway. However, in stress conditions, phosphorylation of the eukaryotic initiation factor 2 (eIF2) allows the expression of several stress-responsive proteins via uORF-mediated mechanisms, while global mRNA translation is inhibited. During endoplasmic reticulum (ER) stress, the accumulation of unfolded proteins leads to activation of the ER-resident PKR-like ER kinase (PERK), which will phosphorylate the α-subunit of eIF2 as part of the stress-protective mechanisms of the unfolded protein response (UPR) and integrated stress response (ISR). This results in selective uORF-mediated translation of downstream effectors, which will drive stress resolution or cell death in case of prolonged stress. The dual role of PERK in regulating cell fate is implicated in a growing list of pathophysiological conditions, including neurological and cardiovascular diseases, ophthalmological disorders, viral infections, cancer, and diabetes. Moreover, mutations in the EIF2AK3 gene encoding PERK are implicated in a rare autosomal recessive disorder, the Wolcott-Rallison Syndrome (WRS). Data from ribosome-profiling (Ribo-seq) studies indicate the existence of uORFs within PERK 5’UTR which could be involved in regulating PERK expression. This work aims to study the translational regulatory role of the uORFs identified in PERK’s 5’UTR and estimate its impact on cell homeostasis and human disease. We wish to highlight the importance of including 5’UTRs in the screening of disease-related mutations, as well as the necessity of functional studies to assess their relevance in the pathogenesis of human diseases, as it may provide vital information for developing new therapeutic strategies.