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Sirtuins are NAD+-dependent deacetylases that facilitate cellular stress response. They include SirT6, which protects genome stability and regulates metabolic homeostasis through gene silencing, and whose loss induces an accelerated aging phenotype directly linked to hyperactivation of the NF-κB pathway. Here we show that SirT6 binds to the H3K9me3- specific histone methyltransferase Suv39h1 and induces monoubiquitination of conserved cysteines in the PRE-SET domain of Suv39h1. Following activation of NF-κB signaling Suv39h1 is released from the IκBα locus, subsequently repressing the NF-κB pathway. We propose that SirT6 attenuates the NF-κB pathway through IκBα upregulation via cysteine monoubiquitination and chromatin eviction of Suv39h1. We suggest a mechanism based on SirT6-mediated enhancement of a negative feedback loop that restricts the NF-κB pathway. [ABSTRACT FROM AUTHOR]

Pericentric heterochromatin (PCH) plays an essential role in the maintenance of genome integrity and alterations in PCH have been linked to cancer and aging. HP1 α, β, and γ, are hallmarks of constitutive heterochromatin that are thought to promote PCH structure through binding to heterochromatin-specific histone modifications and interaction with a wide range of factors. Among the less understood components of PCH is the histone H2A variant H2A.Z, whose role in the organization and maintenance of PCH is poorly defined. Here we show that there is a complex interplay between H2A.Z and HP1 isoforms in PCH. While the loss of HP1α results in the accumulation of H2A.Z.1 in PCH, which is associated with a significant decrease in its mobile fraction, H2A.Z.1 binds preferentially to HP1β in these regions. Of note, H2A.Z.1 downregulation results in increased heterochromatinization and instability of PCH, reflected by accumulation of the major epigenetic hallmarks of heterochromatin in these regions and increased frequency of chromosome aberrations related to centromeric/pericentromeric defects. Our studies support a role for H2A.Z in genome stability and unveil a key role of H2A.Z in the regulation of heterochromatin-specific epigenetic modifications through a complex interplay with the HP1 isoforms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 González, Bosch-Presegué, Marazuela-Duque, Guitart-Solanes, Espinosa-Alcantud, Fernandez, Brown, Ausió, Vazquez, Singh, Fraga and Vaquero.)

Among the greatest challenges facing organisms is that of detecting and effectively responding to life-threatening environmental changes that are intimately associated with metabolic fluctuations and certain forms of stress. These conditions have been linked to the onset of many human pathologies, including cancer. Over the past decade, members of the Sir2 family, or sirtuins, have been described as major players in sensing and coordinating stress response. Evidence has imputed mammalian sirtuins in carcinogenesis, although the mechanisms involved seem to be more diverse and complex than previously anticipated. Some sirtuins, such as SirT2 and SirT6, seem to work as tumor suppressors, but others, such as SirT1, are apparently bifunctional: operating as both tumor suppressors and oncogenic factors depending on the context and the study conditions. The mechanisms underlying these apparently contradictory activities are not well understood, although recent findings suggest that they might actually be two sides of the same coin. In this review, the authors summarize current knowledge on the functional implications of sirtuins in cancer and discuss possible explanations for their functional duality.