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      An Expansion of the Endoplasmic Reticulum that Halts Autophagy is Permissive to Genome Instability

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          Abstract

          The links between autophagy and genome stability, and whether they are important for lifespan and health, are not fully understood. We undertook a study to explore this notion at the molecular level using Saccharomyces cerevisiae. On the one hand, we triggered autophagy using rapamycin, to which we exposed mutants defective in preserving genome integrity, then assessed their viability, their ability to induce autophagy and the link between these two parameters. On the other hand, we searched for molecules derived from plant extracts known to have powerful benefits on human health to try to rescue the negative effects rapamycin had against some of these mutants. We uncover that autophagy execution is lethal for mutants unable to repair DNA double strand breaks, while the extract from Silybum marianum seeds induces an expansion of the endoplasmic reticulum (ER) that blocks autophagy and protects them. Our data uncover a connection between genome integrity and homeostasis of the ER whereby ER stress-like scenarios render cells tolerant to sub-optimal genome integrity conditions.

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          Signal integration in the endoplasmic reticulum unfolded protein response.

          The endoplasmic reticulum (ER) responds to the accumulation of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways - cumulatively called the unfolded protein response (UPR). Together, at least three mechanistically distinct arms of the UPR regulate the expression of numerous genes that function within the secretory pathway but also affect broad aspects of cell fate and the metabolism of proteins, amino acids and lipids. The arms of the UPR are integrated to provide a response that remodels the secretory apparatus and aligns cellular physiology to the demands imposed by ER stress.
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            The endoplasmic reticulum: structure, function and response to cellular signaling

            The endoplasmic reticulum (ER) is a large, dynamic structure that serves many roles in the cell including calcium storage, protein synthesis and lipid metabolism. The diverse functions of the ER are performed by distinct domains; consisting of tubules, sheets and the nuclear envelope. Several proteins that contribute to the overall architecture and dynamics of the ER have been identified, but many questions remain as to how the ER changes shape in response to cellular cues, cell type, cell cycle state and during development of the organism. Here we discuss what is known about the dynamics of the ER, what questions remain, and how coordinated responses add to the layers of regulation in this dynamic organelle.
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              Extending healthy life span--from yeast to humans.

              When the food intake of organisms such as yeast and rodents is reduced (dietary restriction), they live longer than organisms fed a normal diet. A similar effect is seen when the activity of nutrient-sensing pathways is reduced by mutations or chemical inhibitors. In rodents, both dietary restriction and decreased nutrient-sensing pathway activity can lower the incidence of age-related loss of function and disease, including tumors and neurodegeneration. Dietary restriction also increases life span and protects against diabetes, cancer, and cardiovascular disease in rhesus monkeys, and in humans it causes changes that protect against these age-related pathologies. Tumors and diabetes are also uncommon in humans with mutations in the growth hormone receptor, and natural genetic variants in nutrient-sensing pathways are associated with increased human life span. Dietary restriction and reduced activity of nutrient-sensing pathways may thus slow aging by similar mechanisms, which have been conserved during evolution. We discuss these findings and their potential application to prevention of age-related disease and promotion of healthy aging in humans, and the challenge of possible negative side effects.
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                Author and article information

                Journal
                Contact (Thousand Oaks)
                Contact (Thousand Oaks)
                CTC
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                Contact
                SAGE Publications (Sage CA: Los Angeles, CA )
                2515-2564
                22 February 2023
                Jan-Dec 2023
                : 6
                : 25152564231157706
                Affiliations
                [1 ]Ringgold 56221, universityInstitut de Génétique Humaine (IGH); , Université de Montpellier-Centre National de la Recherche Scientifique, Montpellier, France
                [2 ]Ringgold 56219, universityCentre de Recherche en Biologie cellulaire de Montpellier (CRBM); , Université de Montpellier-Centre National de la Recherche Scientifique, Montpellier, France
                Author notes
                [*]María Moriel-Carretero, Centre de Recherche en Biologie cellulaire de Montpellier (CRBM), Université de Montpellier-Centre National de la Recherche Scientifique, Montpellier cedex 5, France. Email: maria.moriel@ 123456crbm.cnrs.fr
                Author information
                https://orcid.org/0000-0002-6770-3486
                Article
                10.1177_25152564231157706
                10.1177/25152564231157706
                10243512
                9b1e777c-605c-4f10-ad52-c14b5b5f9639
                © The Author(s) 2023

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 23 September 2022
                : 27 January 2023
                : 27 January 2023
                Funding
                Funded by: ATIP-Avenir;
                Funded by: Agence Nationale de la Recherche, FundRef https://doi.org/10.13039/501100001665;
                Award ID: ANR-21-CE12-0004-01
                Funded by: Fondation L’Oréal-UNESCO;
                Award ID: FWIS program
                Funded by: Institut National Du Cancer, FundRef https://doi.org/10.13039/501100006364;
                Award ID: PLBIO19-098 INCA_13832
                Categories
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                Custom metadata
                ts19
                January-December 2023

                endoplasmic reticulum,autophagy,genome instability,dna dsbs,homologous recombination,silybum marianum

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