title: SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair.
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.
authors.affiliation: Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ, USA.
authors.forename: Berta N
authors.initials: BN
authors.lastname: Vazquez
authors.affiliation: Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ, USA.
authors.forename: Joshua K
authors.initials: JK
authors.lastname: Thackray
authors.affiliation: Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: Nicolas G
authors.initials: NG
authors.lastname: Simonet
authors.affiliation: Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ, USA.
authors.forename: Noriko
authors.initials: N
authors.lastname: Kane-Goldsmith
authors.affiliation: Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Martinez-Redondo
authors.affiliation: Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ, USA.
authors.forename: Trang
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Bunting
authors.affiliation: Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Vaquero
authors.affiliation: Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ, USA.
authors.forename: Jay A
authors.initials: JA
authors.lastname: Tischfield
authors.affiliation: Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ, USA serrano@biology.rutgers.edu.
authors.forename: Lourdes
authors.identifier: 0000-0002-3409-9366
authors.initials: L
authors.lastname: Serrano
mesh_terms: D000818:Animals; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D059766:DNA End-Joining Repair; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D037761:Sirtuins / Q000378:metabolism*
chemical_list: C539736:Sirt7 protein, mouse; D004247:DNA; D037761:Sirtuins
keywords: DNA damage; PARP1; SIRT7; histone acetylation; non‐homologous end joining