Simonet, Nicolás G.Thackray, Joshua K.Vazquez, Berta N.Ianni, AlessandroEspinosa Alcantud, MariaMorales Sanfrutos, JuliaHurtado-Bagès, Sarah, 1990-Sabidó Aguadé, EduardBuschbeck, MarcusTischfield, JayTorre Gómez, Carolina de laEsteller, ManelBraun, ThomasOlivella, MireiaSerrano, LourdesVaquero, Alejandro2020-11-052020-11-052020-07-242375-2548https://hdl.handle.net/2445/171766Sirtuins 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.16 p.application/pdfengcc-by-nc (c) Simonet et al., 2020http://creativecommons.org/licenses/by-nc/3.0/esEstrès (Fisiologia)Trastorns del metabolismeHomeòstasiStress (Physiology)Disorders of metabolismHomeostasisinfo:eu-repo/semantics/article7024282020-11-05info:eu-repo/semantics/openAccess32832656