SirT7 auto-ADP-ribosylation regulates glucose starvation response through mH2A1

Simonet, Nicolás G.; Thackray, Joshua K.; Vázquez, Berta N.; Ianni, Alessandro; Espinosa Alcantud, Maria; Morales Sanfrutos, Julia; Hurtado-Bagès, Sarah, 1990-; Sabidó Aguadé, Eduard, 1981-; Buschbeck, Marcus; Tischfield, Jay; Torre, Carolina de la; Esteller, Manel; Braun, Thomas; Olivella, Mireia; Serrano, Lourdes; Vaquero, Alejandro

doi:http://dx.doi.org/10.1126/sciadv.aaz2590

SirT7 auto-ADP-ribosylation regulates glucose starvation response through mH2A1

Citation

Simonet NG, Thackray JK, Vazquez BN, Ianni A, Espinosa-Alcantud M, Morales-Sanfrutos J, Hurtado-Bagès S, Sabidó E, Buschbeck M, Tischfield J, De La Torre C, Esteller M, Braun T, Olivella M, Serrano L, Vaquero A. SirT7 auto-ADP-ribosylation regulates glucose starvation response through mH2A1. Sci Adv. 2020; 6(30):eaaz2590. DOI: 10.1126/sciadv.aaz2590

Abstract

Sirtuins are key players of metabolic stress response. Originally described as deacetylases, some sirtuins also exhibit poorly understood mono-adenosine 5'-diphosphate (ADP)-ribosyltransferase (mADPRT) activity. We report that the deacetylase SirT7 is a dual sirtuin, as it also features auto-mADPRT activity. SirT7 mADPRT occurs at a previously undefined active site, and its abrogation alters SirT7 chromatin distribution. We identify an epigenetic pathway by which ADP-ribosyl-SirT7 is recognized by the ADP-ribose reader mH2A1.1 under glucose starvation, inducing SirT7 relocalization to intergenic regions. SirT7 promotes mH2A1 enrichment in a subset of nearby genes, many of them involved in second messenger signaling, resulting in their specific up- or down-regulation. The expression profile of these genes under calorie restriction is consistently abrogated in SirT7-deficient mice, resulting in impaired activation of autophagy. Our work provides a novel perspective on sirtuin duality and suggests a role for SirT7/mH2A1.1 axis in glucose homeostasis and aging.