Genotoxic stress triggers the selective activation of IRE1α-dependent RNA decay to modulate the DNA damage response. Genotoxic stress triggers the selective activation of IRE1α-dependent RNA decay to modulate the DNA damage response

The molecular connections between homeostatic systems that sustain genome integrity and proteostasis are poorly understood. Here we identified the selective activation of the unfolded protein response transducer IRE1α under genotoxic stress to engage repair programs and sustain cell survival. DNA damage engages IRE1 signaling in the absence of an endoplasmic reticulum (ER) stress signature, leading to the exclusive activation of regulated IRE1α-dependent decay (RIDD) and not its canonical output mediated by the transcription factor XBP1. IRE1α controls the stability of mRNAs involved in the DNA damage response, impacting DNA repair, cell cycle arrest and apoptosis. The protective role of IRE1α under genotoxic stress is conserved in evolution as demonstreated using fly and mouse models. Altogether, our results uncovered a novel intersection between the molecular pathways that ensure genome stability and proteostasis. Affymetrix gene expression data were pre-processed using ‘affyPLM’ packages of the Bioconductor Software. Genes with the strongest evidence of differential expression were obtained using a linear model fit. Data obtained from untreated wild type or IRE1αcKO after ploy I:C treatment liver tissues were used as reference for tunicamycin (Tm) and etoposide (Eto) treatment respectively. Custom chip definition file version 22 from Brainarray based on Entrez ID’s was used. A false positive rate of a=0.05 with FDR correction and a fold change greater 1.5 was taken as the level of significance. Overall design: Liver tissue were obteined from a conditional knockout (cKO) mice controlled by the Mx-Cre system for the deletion of IRE1a gene. Poly[I:C] was injected to induce Cre expression, and three weeks later animals were treated with a single dose of either etoposide or tunicamycin, followed by the analysis of gene expression of liver tissues. WT IRE1 = Mice with the full expression of IRE1a (ERN1), KO IRE1= Mice wiht IRE1a (ERN1) deletion, WT IRE1 Eto 50ug 16h= Mice with the full expression of IRE1a (ERN1) treated with Etoposide 50ug/kg for 16 hours, WT IRE1 Tm 1ug 16h= Mice with the full expression of IRE1a (ERN1) treated with Tunicamicyn 1ug/kg for 16 hours, Fi/Fi Cre WT Eto50ug 6h=Mice with the full expression of IRE1a (ERN1) treated with Etoposide 50ug/kg for 6 hours,Fi/Fi Cre WT Tm1ug 6h=Mice with the full expression of IRE1a (ERN1) treated with Tunicamicyn 1ug/kg for 6 hours, KO IRE1 Eto 50ug 16h= Mice wiht IRE1a (ERN1) deletion,treated with Etoposide 50ug/kg for 16 hours, KO IRE1 Tm 1ug 16h= Mice wiht IRE1a (ERN1) deletion,treated with Tunicamicyn 1ug/kg for 16 hours, Fi/Fi Cre KO Eto 50ug 6h= Mice wiht IRE1a (ERN1) deletion,treated with Etoposide 50ug/kg for 6 hours,Fi/Fi Cre KO Tm 1ug 6h=Mice wiht IRE1a (ERN1) deletion, treated with Tunicamicyn 1ug/kg for 6 hours, WT IRE1 untreat = Mice with the full expression of IRE1a (ERN1) with DMSO, KO IRE1 untreat= Mice wiht IRE1a (ERN1) deletion with DMSO, Fi/Fi Cre WT untreat= Mice with the full expression of IRE1a (ERN1) with DMSO, Fi/Fi Cre KO untreat= Mice wiht IRE1a (ERN1) deletion with DMSO