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

TitleGenotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response.
Publication TypeJournal Article
Year of Publication2020
AuthorsDufey E, San Pedro JManuel Bra, Eggers C, González-Quiroz M, Urra H, Sagredo AI, Sepulveda D, Pihán P, Carreras-Sureda A, Hazari Y, Sagredo EA, Gutierrez D, Valls C, Papaioannou A, Acosta-Alvear D, Campos G, Domingos PM, Pedeux R, Chevet E, Alvarez A, Godoy P, Walter P, Glavic A, Kroemer G, Hetz C
JournalNat Commun
Volume11
Issue1
Pagination2401
Date Published2020 May 14
ISSN2041-1723
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.

DOI10.1038/s41467-020-15694-y
Alternate JournalNat Commun
PubMed ID32409639
PubMed Central IDPMC7224204
Grant List16I10223 / / Ministry of Education, Government of Chile | National Commission for Scientific and Technological Research | Fondo de Fomento al Desarrollo Científico y Tecnológico (FONDEF) /
11E1007 / / Ministry of Education, Government of Chile | National Commission for Scientific and Technological Research | Fondo de Fomento al Desarrollo Científico y Tecnológico (FONDEF) /
FA9550-16-1-0384 / / United States Department of Defense | U.S. Air Force (United States Air Force) /