Abstract:Sirtuins are NAD(+)-dependent protein deacetylases that connect metabolism and cellular homeostasis. Here we show that the nuclear Sirtuin SIRT7 targets PAF53, a subunit of RNA polymerase I (Pol I). Acetylation of PAF53 at lysine 373 by CBP and deacetylation by SIRT7 modulate the association of Pol I with DNA, hypoacetylation correlating with increased rDNA occupancy of Pol I and transcription activation. SIRT7 is released from nucleoli in response to different stress conditions, leading to hyperacetylation of… Show more
“…It has been reported previously that stress‐dependent re‐localization of SIRT7 from nucleoli to other nuclear regions leads to a decrease in PolI activity and reduced ribosomal gene transcription (Chen et al , 2013). However, whether SIRT7 acquires novel functions under stress conditions remained unexplored.…”
Section: Discussionmentioning
confidence: 95%
“…SIRT7 has been functionally linked to transcriptional regulation. SIRT7 is detected at promoters and coding regions of ribosomal genes, where it positively controls ribosome production through direct interaction with the PolI machinery (Ford et al , 2006; Grob et al , 2009; Chen et al , 2013). Conversely, SIRT7 negatively regulates the transcription of genes outside of the rDNA repeats via histone H3K18 deacetylation (Barber et al , 2012).…”
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.
“…It has been reported previously that stress‐dependent re‐localization of SIRT7 from nucleoli to other nuclear regions leads to a decrease in PolI activity and reduced ribosomal gene transcription (Chen et al , 2013). However, whether SIRT7 acquires novel functions under stress conditions remained unexplored.…”
Section: Discussionmentioning
confidence: 95%
“…SIRT7 has been functionally linked to transcriptional regulation. SIRT7 is detected at promoters and coding regions of ribosomal genes, where it positively controls ribosome production through direct interaction with the PolI machinery (Ford et al , 2006; Grob et al , 2009; Chen et al , 2013). Conversely, SIRT7 negatively regulates the transcription of genes outside of the rDNA repeats via histone H3K18 deacetylation (Barber et al , 2012).…”
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.
“…On the other hand, SIRT7, another SIRT family member, was reported to activate rRNA transcription depending on the deacetylation activity, through regulation of PAF53, which is an important component of Pol I complex [87][88][89][90][91].…”
The ribosome is a unique machine for protein synthesis in organisms. The construction of ribosomes is exceedingly complex and consumes the majority of the cell materials and energy. The materials for ribosome production are supplied by nutrients. Therefore, the production of ribosomes is restricted by environmental nutrients, and cells need mechanisms to control ribosome production in order to reconcile demands for cell activities with available resources. Transcription of ribosomal RNA is an essential step in ribosome biogenesis. It strongly affects the total amount of ribosome production, and thus rapidly growing cells have an elevated level of ribosomal RNA transcription. Ribosomal RNA transcription is controlled by many mechanisms, including the efficiency of preinitiation complex formation for RNA polymerase I (Pol I) and epigenetic marks in ribosomal RNA genes. These are affected by cell cycle progression, signal transduction pathways, cell-damaging stresses, nutrients such as glucose, and the metabolites. Recent studies also suggest that the epigenetic marks, acetylation and methylation, may be not only controlled by nutrients but also function as reservoirs for biological resources in chromatin. Further studies would provide information about the mechanisms cells use to adjust production of cellular components to available resources and clues for developing novel anti-cancer treatments.
“…[87][88][89][90][91] a Primary subcellular localization is given first, additionally described localization is given in brackets. Enriched in the nucleolus, SIRT7 exhibits deacetylase activity towards a limited set of targets, which are primarily involved in ribosomal DNA transcription [88,92], stabilization of cancer cell phenotypes [87,[93][94][95], and mitochondrial biogenesis and function [91].…”
Section: Sirtuins: Nad+-dependent Enzymes With Different Activities Amentioning
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