期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-15694-y
关键词
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资金
- ANID/FONDAP [15150012]
- Millennium Institute [P09-015-F]
- CONICYT-Brazil [441921/2016-7]
- FONDEF [ID16I10223, D11E1007]
- FONDECYT [1180186, 11180825, 3190738, 3180427, 3150113, 1161065, AFB170005]
- Ecos-Conicyt [C17S02]
- U.S. Air Force Office of Scientific Research [FA9550-16-1-0384]
- Muscular Dystrophy Association
- US Office of Naval Research-Global (ONR-G) [N62909-16-1-2003]
- European Commission RD [MSCA-RISE-734749]
- EMBO ASTF [385-2016]
- CONICYT [2016-21160232]
- MSCA [RISE-734749]
- Cancer Research Institute
- Ligue contre le Cancer (equipe labellisee)
- Agence National de la Recherche (ANR)-Projets blancs
- ANR under the frame of E-Rare-2
- ERA-Net for Research on Rare Diseases
- Association pour la recherche sur le cancer (ARC)
- Canceropole Ile-de-France
- Chancelerie des universites de Paris (Legs Poix)
- Fondation pour la Recherche Medicale (FRM)
- European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR)
- European Research Council (ERC)
- Fondation Carrefour
- Institut National du Cancer (INCa)
- Inserm
- Institut Universitaire de France
- LeDucq Foundation
- LabEx Immuno-Oncology
- RHU Torino Lumiere
- Seerave Foundation
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- Paris Alliance of Cancer Research Institutes (PACRI)
- Fondation pour la Recherche Medicale (FMR) [DEQ20180339169]
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Institut National du Cancer (INCa PLBIO), ANR under the frame of ERANET (ERAAT)
- EU H2020 MSCA [ITN-675448]
- [FONDAP-GERO-15150012]
- [FONDAP-CRG-15090007]
- [ACT1401]
- [FCT LISBOA-01-0145-FEDER-007660]
- [PTDC/NEU-NMC/2459/2014]
- [IF/00697/2014]
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 IRE1 alpha under genotoxic stress to modulate repair programs and sustain cell survival. DNA damage engages IRE1 alpha signaling in the absence of an endoplasmic reticulum (ER) stress signature, leading to the exclusive activation of regulated IRE1 alpha -dependent decay (RIDD) without activating its canonical output mediated by the transcription factor XBP1. IRE1 alpha 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 IRE1 alpha to catalyze RIDD. The protective role of IRE1 alpha 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. IRE1 alpha plays a key role in the unfolded protein response (UPR) by promoting the unconventional splicing of the XBP1 and the selective cleavage of RNAs. Here the authors report that IRE1 alpha is activated upon the DNA damage response and selectively controls the stability of mRNAs to maintain genome integrity.
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