SirT7 auto-ADP-ribosylation regulates glucose starvation response through macroH2A1.1

Simonet, N. G.; Thackray, J. K.; Vazquez, B. N.; Ianni, A.; Espinosa-Alcantud, M.; Morales-Sanfrutos, J.; Hurtado-Bages, S.; Sabido, E.; Buschbeck, M.; Tischfield, J.; de la Torre, C.; Esteller, M.; Braun, T.; Olivella, M.; Serrano, L.; Vaquero, A.

doi:10.1101/719559

bioRxiv · 10.1101/719559

SirT7 auto-ADP-ribosylation regulates glucose starvation response through macroH2A1.1

Simonet, N. G.·Thackray, J. K.·Vazquez, B. N.·Ianni, A.·Espinosa-Alcantud, M.·Morales-Sanfrutos, J.·Hurtado-Bages, S.·Sabido, E.·Buschbeck, M.·Tischfield, J.·de la Torre, C.·Esteller, M.·Braun, T.·Olivella, M.·Serrano, L.·Vaquero, A.

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Abstract

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 ADP-ribosyl-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, N. G., Thackray, J. K., Vazquez, B. N., Ianni, A., Espinosa-Alcantud, M., Morales-Sanfrutos, J., Hurtado-Bages, S., Sabido, E., Buschbeck, M., Tischfield, J., de la Torre, C., Esteller, M., Braun, T., Olivella, M., Serrano, L., Vaquero, A.. 2019-08-05. SirT7 auto-ADP-ribosylation regulates glucose starvation response through macroH2A1.1. https://doi.org/10.1101/719559

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