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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/171766
SirT7 auto-ADP-ribosylation regulates glucose starvation response through macroH2A1
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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.
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SIMONET, Nicolás g., THACKRAY, Joshua k., VAZQUEZ, Berta n., IANNI, Alessandro, ESPINOSA ALCANTUD, Maria, MORALES SANFRUTOS, Julia, HURTADO-BAGÈS, Sarah, SABIDÓ AGUADÉ, Eduard, BUSCHBECK, Marcus, TISCHFIELD, Jay, TORRE GÓMEZ, Carolina de la, ESTELLER, Manel, BRAUN, Thomas, OLIVELLA, Mireia, SERRANO, Lourdes, VAQUERO, Alejandro. SirT7 auto-ADP-ribosylation regulates glucose starvation response through macroH2A1. _Science Advances_. 2020. Vol. 6, núm. eaaz2590. [consulta: 25 de novembre de 2025]. ISSN: 2375-2548. [Disponible a: https://hdl.handle.net/2445/171766]