Browsing by Author "Urra, Hery"

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    Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response
    (2020) Dufey, Estefanie; Bravo-San Pedro, Jose Manuel; Eggers, Cristian; Gonzalez-Quiroz, Matias; Urra, Hery; Sagredo, Alfredo, I; Sepulveda, Denisse; Pihan, Philippe; Carreras-Sureda, Amado; Hazari, Younis; Sagredo, Eduardo A.; Gutierrez, Daniela; Valls, Cristian; Papaioannou, Alexandra; Acosta-Alvear, Diego; Campos, Gisela; Domingos, Pedro M.; Pedeux, Remy; Chevet, Eric; Alvarez, Alejandra; Godoy, Patricio; Walter, Peter; Glavic, Alvaro; Kroemer, Guido; Hetz, Claudio
    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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    Helicobacter pylori-Induced Loss of the Inhibitor-of-Apoptosis Protein Survivin Is Linked to Gastritis and Death of Human Gastric Cells
    (OXFORD UNIV PRESS INC, 2010) Valenzuela, Manuel; Perez Perez, Guillermo; Corvalan, Alejandro H.; Carrasco, Gonzalo; Urra, Hery; Bravo, Denisse; Toledo, Hector; Quest, Andrew F. G.
    Helicobacter pylori infects the human stomach and modifies signaling pathways that affect gastric epithelial cell proliferation and viability. Chronic exposure to this pathogen contributes to the onset of gastric atrophy, an early event in the genesis of gastric cancer associated with H. pylori infection. Susceptibility to H. pylori-induced cell death ultimately depends on the presence of protective host cell factors. Although expression of the inhibitor-of-apoptosis protein survivin in adults is frequently linked to the development of cancer, evidence indicating that the protein is present in normal gastric mucosa is also available. Thus, we investigated in human gastric tissue samples and cell lines whether H. pylori infection is linked to loss of survivin and increased cell death. Our results show that infection with H. pylori decreased survivin protein levels in the mucosa of patients with gastritis. Furthermore, survivin down-regulation correlated with apoptosis and loss of cell viability in gastrointestinal cells cocultured with different H. pylori strains. Finally, overexpression of survivin in human gastric cells was sufficient to reduce cell death after infection. Taken together, these findings implicate survivin as an important survival factor in the gastric mucosa of humans.