Browsing by Author "Sagredo, Eduardo A."

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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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    Increase in ADAR1p110 activates the canonical Wnt signaling pathway associated with aggressive phenotype in triple negative breast cancer cells
    (2022) Morales, Fernanda; Perez, Paola; Tapia, Julio C.; Lobos-Gonzalez, Lorena; Manuel Herranz, Jose; Guevara, Francisca; Rojas de Santiago, Pamela; Palacios, Esteban; Andaur, Rodrigo; Sagredo, Eduardo A.; Marcelain, Katherine; Armisen, Ricardo
    Triple-negative breast cancer (TNBC) represents a challenge in the search for new therapeutic targets. TNBCs are aggressive and generate resistance to chemotherapy. Tumors of TNBC patients with poor prognosis present a high level of adenosine deaminase acting on RNA1 (ADAR1). We explore the connection of ADAR1 with the canonical Wnt signaling pathway and the effect of modulation of its expression in TNBC. Expression data from cell line sequencing (DepMap) and TCGA samples were downloaded and analyzed. We lentivirally generated an MDA-MB-231 breast cancer cell line that overexpress (OE) ADAR1p110 or an ADAR knockdown. Abundance of different proteins related to Wnt/beta-catenin pathway and activity of nuclear beta-catenin were analyzed by Western blot and luciferase TOP/FOP reporter assay, respectively. Cell invasion was analyzed by matrigel assay. In mice, we study the behavior of tumors generated from ADAR1p110 (OE) cells and tumor vascularization immunostaining were analyzed. ADAR1 connects to the canonical Wnt pathway in TNBC. ADAR1p110 overexpression decreased GSK-3 beta, while increasing active beta-catenin. It also increased the activity of nuclear beta-catenin and increased its target levels. ADAR1 knockdown has the opposite effect. MDA-MB-231 ADAR1 (OE) cells showed increased capacity of invasion. Subsequently, we observed that tumors derived from ADAR1p110 (OE) cells showed increased invasion towards the epithelium, and increased levels of Survivin and CD-31 expressed in vascular endothelial cells. These results indicate that ADAR1 overexpression alters the expression of some key components of the canonical Wnt pathway, favoring invasion and neovascularization, possibly through activation of the beta-catenin, which suggests an unknown role of ADAR1p110 in aggressiveness of TNBC tumors.