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

Estefanie Dufey 1 José Manuel Bravo-San Pedro 2 Cristian Eggers 1 Matías González-Quiroz 1, 3, 4 Hery Urra 1 Alfredo I Sagredo 1 Denisse Sepulveda 1 Philippe Pihán 1 Amado Carreras-Sureda 1 Younis Hazari 1 Eduardo A Sagredo 5 Daniela Gutierrez 6 Cristian Valls 6 Alexandra Papaioannou 3, 4 Diego Acosta-Alvear 7, 8 Gisela Campos 9, 10 Pedro M Domingos 11 Remy Pedeux 3, 4 Eric Chevet 3, 4 Alejandra Alvarez 6 Patricio Godoy 10 Peter Walter 7 Álvaro Glavic 1 Guido Kroemer 2, 12, 13 Claudio Hetz 1
1 UCHILE - Universidad de Chile = University of Chile [Santiago]
2 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
3 COSS - Chemistry, Oncogenesis, Stress and Signaling
4 CRLCC - Centre Eugène Marquis
5 Stockholm University
6 UC - Pontificia Universidad Católica de Chile
7 University of the Pacific [San Francisco]
8 UCSB - University of California [Santa Barbara]
9 TU - Technische Universität Dortmund [Dortmund]
10 IFADO - Leibniz Research Centre for Working Environment and Human Factors [Dortmund]
11 NOVA - Universidade Nova de Lisboa = NOVA University of Lisboa
12 Pôle de biologie
13 Karolinska Institutet [Stockholm]
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.
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-02862260
Contributor : Laurent Jonchère <>
Submitted on : Tuesday, June 9, 2020 - 1:43:44 PM
Last modification on : Tuesday, July 21, 2020 - 3:50:20 AM

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Estefanie Dufey, José Manuel Bravo-San Pedro, Cristian Eggers, Matías González-Quiroz, Hery Urra, et al.. Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response. Nature Communications, Nature Publishing Group, 2020, 11 (1), pp.2401. ⟨10.1038/s41467-020-15694-y⟩. ⟨hal-02862260⟩

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