Browsing by Author "Eggers, Cristian"

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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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    p53 Related Protein Kinase is Required for Arp2/3-Dependent Actin Dynamics of Hemocytes in Drosophila melanogaster
    (2022) Molina, Emiliano; Cataldo, Vicente F.; Eggers, Cristian; Munoz-Madrid, Valentina; Glavic, Alvaro
    Cells extend membrane protrusions like lamellipodia and filopodia from the leading edge to sense, to move and to form new contacts. The Arp2/3 complex sustains lamellipodia formation, and in conjunction with the actomyosin contractile system, provides mechanical strength to the cell. Drosophila p53-related protein kinase (Prpk), a Tsc5p ortholog, has been described as essential for cell growth and proliferation. In addition, Prpk interacts with proteins associated to actin filament dynamics such as alpha-spectrin and the Arp2/3 complex subunit Arpc4. Here, we investigated the role of Prpk in cell shape changes, specifically regarding actin filament dynamics and membrane protrusion formation. We found that reductions in Prpk alter cell shape and the structure of lamellipodia, mimicking the phenotypes evoked by Arp2/3 complex deficiencies. Prpk co-localize and co-immunoprecipitates with the Arp2/3 complex subunit Arpc1 and with the small GTPase Rab35. Importantly, expression of Rab35, known by its ability to recruit upstream regulators of the Arp2/3 complex, could rescue the Prpk knockdown phenotypes. Finally, we evaluated the requirement of Prpk in different developmental contexts, where it was shown to be essential for correct Arp2/3 complex distribution and actin dynamics required for hemocytes migration, recruitment, and phagocytosis during immune response.