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 Alvarez, Patricio Godoy, Peter Walter, Alvaro Glavic, Guido Kroemer and Claudio Hetz ()
Additional contact information
Estefanie Dufey: University of Chile
José Manuel Bravo-San Pedro: Université de Paris, Sorbonne Université
Cristian Eggers: University of Chile
Matías González-Quiroz: University of Chile
Hery Urra: University of Chile
Alfredo I. Sagredo: University of Chile
Denisse Sepulveda: University of Chile
Philippe Pihán: University of Chile
Amado Carreras-Sureda: University of Chile
Younis Hazari: University of Chile
Eduardo A. Sagredo: Stockholm University, Svante Arrheniusväg 20C
Daniela Gutierrez: Pontificia Universidad Católica de Chile
Cristian Valls: Pontificia Universidad Católica de Chile
Alexandra Papaioannou: Proteostasis & Cancer Team, INSERM U1242, University of Rennes 1
Diego Acosta-Alvear: University of California
Gisela Campos: IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund
Pedro M. Domingos: Universidade Nova de Lisboa, Av. da República
Rémy Pedeux: Proteostasis & Cancer Team, INSERM U1242, University of Rennes 1
Eric Chevet: Proteostasis & Cancer Team, INSERM U1242, University of Rennes 1
Alejandra Alvarez: Pontificia Universidad Católica de Chile
Patricio Godoy: IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund
Peter Walter: University of California
Alvaro Glavic: University of Chile
Guido Kroemer: Université de Paris, Sorbonne Université
Claudio Hetz: University of Chile

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15694-y

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