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Abstract
Sirtuins, a family of protein deacetylases, promote cellular homeostasis by mediating communication between cells and environment. The enzymatic activity of the mammalian sirtuin SIRT7 targets acetylated lysine in the N‐terminal tail of histone H3 (H3K18Ac), thus modulating chromatin structure and transcriptional competency. SIRT7 deletion is associated with reduced lifespan in mice through unknown mechanisms. Here, we show that SirT7‐knockout mice suffer from partial embryonic lethality and a progeroid‐like phenotype. Consistently, SIRT7‐deficient cells display increased replication stress and impaired DNA repair. SIRT7 is recruited in a PARP1‐dependent manner to sites of DNA damage, where it modulates H3K18Ac levels. H3K18Ac in turn affects recruitment of the damage response factor 53BP1 to DNA double‐strand breaks (DSBs), thereby influencing the efficiency of non‐homologous end joining (NHEJ). These results reveal a direct role for SIRT7 in DSB repair and establish a functional link between SIRT7‐mediated H3K18 deacetylation and the maintenance of genome integrity.
Highlights
Sirtuins are NAD+-dependent protein deacetylases and, in some cases, NAD+-dependent ADP ribosyltransferases
Our results indicate that SIRT7 participates in the maintenance of genome integrity by modulating DNA repair, the activity of non-homologous end joining (NHEJ) double-strand breaks (DSBs) repair, plausibly by modulating the recruitment of 53BP1 to chromatin
We have demonstrated that genome homeostasis is disrupted in the absence of SIRT7
Summary
Sirtuins are NAD+-dependent protein deacetylases and, in some cases, NAD+-dependent ADP ribosyltransferases. Mammals have seven sirtuin family members, which are denoted SIRT1 to 7. They are involved in sensing and responding to different types of cellular stressors, including fasting, genotoxic, and oxidative stress (Vaquero & Reinberg, 2009). A key function of sirtuins is the regulation and maintenance of genome stability under stress. As this regulation fails, genome integrity can diminish, resulting in devastating consequences on cellular fitness, cumulatively leading to organismal aging. Numerous studies from yeast to mice support a role for sirtuins in the amelioration of human aging-related pathologies (Guarente, 2013), and its deletion is associated with genome instability and compromised organismal viability (Cheng et al, 2003; McBurney et al, 2003; Mostoslavsky et al, 2006; Wang et al, 2008a; Serrano et al, 2013)
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