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

Estefanie Dufey, José Manuel Bravo-San Pedro, Cristian Eggers, Matías González-Quiroz, Hery Urra, Alfredo I. Sagredo, Denisse Sepulveda, Philippe Pihán, Amado Carreras-Sureda, Younis Hazari, Eduardo A. Sagredo, Daniela Gutierrez, Cristian Valls, Alexandra Papaioannou, Diego Acosta-Alvear, Gisela Campos, Pedro M. Domingos, Rémy Pedeux, Eric Chevet, Alejandra AlvarezPatricio Godoy, Peter Walter, Alvaro Glavic, Guido Kroemer, Claudio Hetz

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

The molecular connections between homeostatic systems that maintain both genome integrity and proteostasis are poorly understood. Here we identify the selective activation of the unfolded protein response transducer IRE1α under genotoxic stress to modulate repair programs and sustain cell survival. DNA damage engages IRE1α signaling in the absence of an endoplasmic reticulum (ER) stress signature, leading to the exclusive activation of regulated IRE1α-dependent decay (RIDD) without activating its canonical output mediated by the transcription factor XBP1. IRE1α endoribonuclease activity controls the stability of mRNAs involved in the DNA damage response, impacting DNA repair, cell cycle arrest and apoptosis. The activation of the c-Abl kinase by DNA damage triggers the oligomerization of IRE1α to catalyze RIDD. The protective role of IRE1α under genotoxic stress is conserved in fly and mouse. Altogether, our results uncover an important intersection between the molecular pathways that sustain genome stability and proteostasis.

Original languageEnglish
Article number2401
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 1 Dec 2020

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