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SirT7 auto-ADP-ribosylation regulates glucose starvation response through macroH2A1 Simonet, Nicolás G. Thackray, Joshua K. Vazquez, Berta N. Ianni, Alessandro Espinosa Alcantud, Maria Morales Sanfrutos, Julia Hurtado-Bagès, Sarah, 1990- Sabidó Aguadé, Eduard Buschbeck, Marcus Tischfield, Jay Torre Gómez, Carolina de la Esteller, Manel Braun, Thomas Olivella, Mireia Serrano, Lourdes Vaquero, Alejandro Estrès (Fisiologia) Trastorns del metabolisme Homeòstasi Stress (Physiology) Disorders of metabolism Homeostasis Sirtuins are key players in the response to oxidative, metabolic and genotoxic stress, and are involved in genome stability, metabolic homeostasis and aging. Originally described as NAD+ -dependent deacetylases, some sirtuins are also characterized by a poorly understood mono-ADP-ribosyltransferase (mADPRT) activity. Here we report that the deacetylase SirT7 is a dual sirtuin as it also features auto-mADPRT activity. Molecular and structural evidence suggests that this novel activity occurs at a second previously undefined active site that is physically separated in another domain. Specific abrogation of this activity alters SirT7 chromatin distribution, suggesting a role for this modification in SirT7 chromatin binding specificity. We uncover an epigenetic pathway by which ADPribosyl-SirT7 is recognized by the ADP-ribose reader macroH2A1.1, a histone variant involved in chromatin organization, metabolism and differentiation. Glucose starvation (GS) boosts this interaction and promotes SirT7 relocalization to intergenic regions in a macroH2A1-dependent manner. Both SirT7 activities are in turn required to promote GS-dependent enrichment of macroH2A1 in a subset of nearby genes, which results in their specific up- or downregulation. Consistently, the expression changes of these genes associated to calorie restriction (CR) or aging are abrogated in SirT7-/- mice, reinforcing the link between Sirtuins, CR and aging. Our work provides a novel perspective about sirtuin duality and suggests a key role for SirT7/macroH2A1.1 axis in mammalian glucose homeostasis, calorie restriction signaling and aging. 2020-11-05T12:23:48Z 2020-11-05T12:23:48Z 2020-07-24 2020-11-05T12:23:48Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Reproducció del document publicat a: https://doi.org/10.1126/sciadv.aaz2590 Science Advances, 2020, vol. 6, p. eaaz2590 https://doi.org/10.1126/sciadv.aaz2590 cc-by-nc (c) Simonet et al., 2020 http://creativecommons.org/licenses/by-nc/3.0/es info:eu-repo/semantics/openAccess American Association for the Advancement of Science Articles publicats en revistes (Ciències Fisiològiques)