The TIA1 RNA-binding-protein family regulates EIF2AK2-mediated stress response and cell cycle progression

TIA1 and TIAL1 encode a family of U-rich-sequence-specific mRNA-binding proteins (mRBPs) ubiquitously expressed and conserved in metazoans. By PAR-CLIP, we determined that both proteins bind target sites with identical specificity in 3' UTRs as well as within introns proximal to 5' and 3' splice sites. Double knockout (DKO) of TIA1 and TIAL1 increased target mRNA abundance proportional to the number of binding sites and impacted the accumulation of aberrantly spliced mRNAs including the dsRNA-binding protein PRKRA, whose expression was completely blocked and subsequently triggered the activation of the dsRNA-activated protein kinase EIF2AK2/PKR and stress granule formation. Ectopic expression of PRKRA cDNA or knockout of EIF2AK2 in DKO cells rescued this phenotype. Perturbation of maturation and/or stability of additional targets also compromised cell cycle progression. Our study reveals the essential role of a single mRBP family contributing to fidelity of mRNA maturation, translation and RNA stress sensing pathways in human cells.

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