Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response
Authors: Pedro M Domingos
Claudio Hetz
Alfredo I Sagredo
Matías González-Quiroz
Eric Chevet
Eduardo A Sagredo
Alexandra Papaioannou
Daniela Gutierrez
Cristian Valls
Gisela Campos
Alejandra Alvarez
Hery Urra
Guido Kroemer
Cristian Eggers
Younis Hazari
Alvaro Glavic
Denisse Sepulveda
Diego Acosta-Alvear
Amado Carreras-Sureda
Peter Walter
Estefanie Dufey
José Manuel Bravo-San Pedro
Philippe Pihán
Rémy Pedeux
Patricio Godoy
Journal: Nature Communications (2020)
Discipline: Multidisciplinary
Keywords: genome integrity; proteostasis; unfolded protein response; IRE1α; DNA damage
Affiliations: Biomedical Neuroscience Institute (BNI), Faculty of Medicine, University of Chile, Santiago, Chile., Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile., Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile., Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université de Paris, Sorbonne Université, Paris, France., Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France., Department of Biology, Faculty of Sciences, University of Chile, Santiago, Chile., Center for Genome Regulation, Faculty of Sciences, University of Chile, Santiago, Chile., Proteostasis & Cancer Team, INSERM U1242, University of Rennes 1, Rennes, France., Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France., Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Svante Arrheniusväg 20C, 106 91, Stockholm, Sweden., Department of Cell & Molecular Biology, Pontificia Universidad Católica de Chile, 8331010, Santiago, Chile., Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA., Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA., Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, 93106, USA., IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, 44139, Dortmund, Germany., Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. da República, 2780-157, Oeiras, Portugal., Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France., Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China., Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden., Biomedical Neuroscience Institute (BNI), Faculty of Medicine, University of Chile, Santiago, Chile. ., Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile. ., Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile. ., The Buck Institute for Research in Aging, Novato, CA, 94945, USA. .

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. 

Retracted: No

PubPeer comments:
 Figure 5F confuses me. *** ![file] , 
 Thank you for noticing the error in the presentation of the WBs in figure 5. We have contacted the editorial chief and sent the new figure. In the original submission, the complete membranes have already been submitted for review. In the next few days, the figure without errors will appear in the journal. ,