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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE130952 | GEO | 2019/05/10

REPOSITORIES: GEO

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