SIRT7 promotes genome integrity and modulates non‐homologous end joining DNA repair. (25th May 2016)

• Record Type: Journal Article
• Authors: Vazquez, Berta N; Thackray, Joshua K; Simonet, Nicolas G; Kane‐Goldsmith, Noriko; Martinez‐Redondo, Paloma; Nguyen, Trang; Bunting, Samuel; Vaquero, Alejandro; Tischfield, Jay A; Serrano, Lourdes
• Is Part Of: EMBO journal. Volume 35:Number 14(2016)
• Page Start: 1488
• Page End: 1503
• Publication Date: 2016-05-25
• Subjects: DNA damage -- histone acetylation -- non‐homologous end joining -- PARP1 -- SIRT7; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201593499
• Languages: English
• ISSNs: 0261-4189

Abstract

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. Synopsis: Sirtuins are deacetylase enzymes implicated in genome stability and life span regulation. Here, the roles of SIRT7 in genome function are studied by characterization of SirT7 −/− mice. Loss of SIRT7 results in reduced embryonic viability, accelerated aging, and genomic instability. SIRT7 is recruited to sites of DNA damage in a PARP‐dependent manner. SIRT7 participates in the DNA damage response by promoting NHEJ DNA repair. SIRT7‐dependent H3K18 deacetylation is important for efficient 53BP1 recruitment at DNA damage sites. SIRT7‐deficient cells show increased levels of replication stress, which may underlie progeroid phenotypes. Abstract : Increased replication stress and impaired DNA damage response in SIRT7‐deficient cells are linked to developmental defects and accelerated again in SIRT7 KO mice.