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.
Sirtuins (Sirt1-Sirt7) are NAD + -dependent protein deacetylases/ ADP ribosyltransferases, which play decisive roles in chromatin silencing, cell cycle regulation, cellular differentiation, and metabolism. Different sirtuins control similar cellular processes, suggesting a coordinated mode of action but information about potential cross-regulatory interactions within the sirtuin family is still limited. Here, we demonstrate that Sirt1 requires autodeacetylation to efficiently deacetylate targets such as p53, H3K9, and H4K16. Sirt7 restricts Sirt1 activity by preventing Sirt1 autodeacetylation causing enhanced Sirt1 activity in Sirt7 −/− mice. Increased Sirt1 activity in Sirt7 −/− mice blocks PPARγ and adipocyte differentiation, thereby diminishing accumulation of white fat. Thus, reduction of Sirt1 activity restores adipogenesis in Sirt7 −/− adipocytes in vitro and in vivo. We disclosed a principle controlling Sirt1 activity and uncovered an unexpected complexity in the crosstalk between two different sirtuins. We propose that antagonistic interactions between Sirt1 and Sirt7 are pivotal in controlling the signaling network required for maintenance of adipose tissue.sirtuin | acetylation | adipogenesis T he seven sirtuins in mammals (Sirt1-Sirt7) are involved in the regulation of essential cellular processes. Sirtuins rapidly adjust the activity of chromatin, transcription factors, metabolic enzymes, and structural proteins to cellular needs by deacetylating a broad range of targets. The ability to sense metabolic alterations and various stressors enable sirtuins to adapt cellular homeostasis to varying conditions. It seems likely that this feature of sirtuins is crucial to prevent age-dependent pathologies and promote a healthy lifespan (1, 2).Sirt1 is the most widely studied mammalian sirtuin showing the highest homology to the founding member of the sirtuin family, the yeast silence information regulator, Sir2. Sirt1 deacetylates histones H3K9, H3K56, H4K16, and H1K26 as well as many nonhistone targets thereby contributing to the maintenance of metabolic homeostasis and genomic integrity (3, 4). Sirt1 was also identified as a critical component of lifespan extension in response to calorie restriction in several model organisms, although its exact contribution is still under debate (5). The functions of Sirt7 have attracted less attention compared with Sirt1.
Long interspersed elements-1 (LINE-1, L1) are retrotransposons that hold the capacity of self-propagation in the genome with potential mutagenic outcomes. How somatic cells restrict L1 activity and how this process becomes dysfunctional during aging and in cancer cells is poorly understood. L1s are enriched at lamin-associated domains, heterochromatic regions of the nuclear periphery. Whether this association is necessary for their repression has been elusive. Here we show that the sirtuin family member SIRT7 participates in the epigenetic transcriptional repression of L1 genome-wide in both mouse and human cells. SIRT7 depletion leads to increased L1 expression and retrotransposition. Mechanistically, we identify a novel interplay between SIRT7 and Lamin A/C in L1 repression. Our results demonstrate that SIRT7-mediated H3K18 deacetylation regulates L1 expression and promotes L1 association with elements of the nuclear lamina. The failure of such activity might contribute to the observed genome instability and compromised viability in SIRT7 knockout mice. Overall, our results reveal a novel function of SIRT7 on chromatin organization by mediating the anchoring of L1 to the nuclear envelope, and a new functional link of the nuclear lamina with transcriptional repression.
Adaptation to different forms of environmental stress is crucial for maintaining essential cellular functions and survival. The nucleolus plays a decisive role as a signaling hub for coordinating cellular responses to various extrinsic and intrinsic cues. p53 levels are normally kept low in unstressed cells, mainly due to E3 ubiquitin ligase MDM2-mediated degradation. Under stress, nucleophosmin (NPM) relocates from the nucleolus to the nucleoplasm and binds MDM2, thereby preventing degradation of p53 and allowing cell-cycle arrest and DNA repair. Here, we demonstrate that the mammalian sirtuin SIRT7 is an essential component for the regulation of p53 stability during stress responses induced by ultraviolet (UV) irradiation. The catalytic activity of SIRT7 is substantially increased upon UV irradiation through ataxia telangiectasia mutated and Rad3 related (ATR)-mediated phosphorylation, which promotes efficient deacetylation of the SIRT7 target NPM. Deacetylation is required for stress-dependent relocation of NPM into the nucleoplasm and MDM2 binding, thereby preventing ubiquitination and degradation of p53. In the absence of SIRT7, stress-dependent stabilization of p53 is abrogated, both in vitro and in vivo, impairing cellular stress responses. The study uncovers an essential SIRT7-dependent mechanism for stabilization of the tumor suppressor p53 in response to genotoxic stress.
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.
BackgroundThe specific deposition of histone variants into chromatin is an important epigenetic mechanism that contributes to gene regulation through chromatin architectural changes. The histone variant H2A.Z is essential in higher eukaryotes, and its incorporation within chromatin is a relevant process for gene expression and genome stability. However, the dual positive and negative roles of H2A.Z in gene regulation still remain unclear. We previously reported that acclimatization in common carp fish (Cyprinus carpio) involves cyclical seasonal gene reprogramming as an adaptation response to its natural environment, when rRNA synthesis and processing are profoundly affected. Epigenetic mechanisms primarily contribute to the transcriptional modulation of ribosomal genes concomitant with the acclimatization process, thus significantly regulating this process. The aim of this study was to describe the presence of several H2A.Z subtypes in carp, and assess the role of H2A.Z on the ribosomal cistron in summer- and winter-acclimatized carp.ResultsThis paper reports for the first time about the transcriptional expression of four different H2A.Z subtypes belonging to the same organism. Remarkably, a novel H2A.Z.7 was found, which corresponds to a tissue-specific histone subtype that contains seven amino acid residues longer than the canonical H2A.Z. Moreover, H2A.Z enrichment through the ribosomal cistron was significantly higher during summer, when rRNA transcription and processing are highly active, than it was in winter. Similar patterns of H2A.Z enrichment are found in two seasonally active promoters for genes transcribed by RNA polymerase II, the L41 and Δ9-desaturase genes. Interestingly, ubiquitylated-H2A.Z (H2A.Zub) was strongly enriched on regulatory regions of the ribosomal cistron in summer-acclimatized carp. Additionally, H2A.Z was present in both heterochromatin and euchromatin states on ribosomal cistron and RNA polymerase II promoters.ConclusionsOur study revealed seasonally-dependent H2A.Z enrichment for active ribosomal cistron and RNA polymerase II promoters during the carp environmental adaptation. Moreover, seasonal H2A.Zub enrichment appears as a specific mechanism contributing to the regulation of chromatin architecture under natural conditions. The existence of several H2A.Z subtypes in carp suggests that the epigenetic regulation in this species constitutes a complex and finely tuned mechanism developed to cope with seasonal environmental changes that occur in its habitat.
Sirtuins are crucial proteins involved in sensing and coordinating the response to different forms of stress, mainly through NAD -dependent deacetylation of proteins. For that reason, sirtuins are directly involved in many human pathologies including cancer, diabetes, cardiovascular and neurodegenerative diseases. SirT7, one of the less well-understood sirtuins, has been associated with ribosome biogenesis, gene expression, metabolism and cancer. Despite the wide range of these functions, only a handful of targets for SirT7 have so far been described. In this issue, Zhang et al. report the first proteomic screening of SirT7 substrates. Using stable isotope labeling with amino acids in cell culture (SILAC), coupled with quantitative mass spectrometry, they have identified a comprehensive list of candidates involved in a variety of functions, ranging from maintenance of chromatin architecture to gene silencing and metabolism. A selected group of these candidates has been validated by in vitro co-immunoprecipitation and deacetylation experiments. Predictive tools have identified additional candidates. The identification of these novel targets not only suggests new ways of understanding the physiological role of SirT7, but also provides new evidence to add to our existing knowledge of the global impact of sirtuins in cell homeostasis.
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