title: Genomic instability and aging-like phenotype in the absence of mammalian SIRT6.
abstract: The Sir2 histone deacetylase functions as a chromatin silencer to regulate recombination, genomic stability, and aging in budding yeast. Seven mammalian Sir2 homologs have been identified (SIRT1-SIRT7), and it has been speculated that some may have similar functions to Sir2. Here, we demonstrate that SIRT6 is a nuclear, chromatin-associated protein that promotes resistance to DNA damage and suppresses genomic instability in mouse cells, in association with a role in base excision repair (BER). SIRT6-deficient mice are small and at 2-3 weeks of age develop abnormalities that include profound lymphopenia, loss of subcutaneous fat, lordokyphosis, and severe metabolic defects, eventually dying at about 4 weeks. We conclude that one function of SIRT6 is to promote normal DNA repair, and that SIRT6 loss leads to abnormalities in mice that overlap with aging-associated degenerative processes.
authors.affiliation: Howard Hughes Medical Institute, The Children's Hospital, CBR Institute for Biomedical Research, Harvard University Medical School, Boston, MA 02115, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
authors.forename: Katrin F
authors.initials: KF
authors.lastname: Chua
authors.forename: David B
authors.initials: DB
authors.lastname: Lombard
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Pang
authors.forename: Miriam R
authors.initials: MR
authors.lastname: Fischer
authors.forename: Lionel
authors.initials: L
authors.lastname: Gellon
authors.forename: Pingfang
authors.initials: P
authors.lastname: Liu
authors.forename: Gustavo
authors.initials: G
authors.lastname: Mostoslavsky
authors.forename: Sonia
authors.initials: S
authors.lastname: Franco
authors.forename: Michael M
authors.initials: MM
authors.lastname: Murphy
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Mills
authors.forename: Parin
authors.initials: P
authors.lastname: Patel
authors.forename: Joyce T
authors.initials: JT
authors.lastname: Hsu
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Hong
authors.forename: Ethan
authors.initials: E
authors.lastname: Ford
authors.forename: Hwei-Ling
authors.initials: HL
authors.lastname: Cheng
authors.forename: Caitlin
authors.initials: C
authors.lastname: Kennedy
authors.forename: Nomeli
authors.initials: N
authors.lastname: Nunez
authors.forename: Roderick
authors.initials: R
authors.lastname: Bronson
authors.forename: David
authors.initials: D
authors.lastname: Frendewey
authors.forename: Wojtek
authors.initials: W
authors.lastname: Auerbach
authors.forename: David
authors.initials: D
authors.lastname: Valenzuela
authors.forename: Margaret
authors.initials: M
authors.lastname: Karow
authors.forename: Michael O
authors.initials: MO
authors.lastname: Hottiger
authors.forename: Stephen
authors.initials: S
authors.lastname: Hursting
authors.forename: J Carl
authors.initials: JC
authors.lastname: Barrett
authors.forename: Leonard
authors.initials: L
authors.lastname: Guarente
authors.forename: Richard
authors.initials: R
authors.lastname: Mulligan
authors.forename: Bruce
authors.initials: B
authors.lastname: Demple
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000473:pathology; D042822:Genomic Instability; D006801:Humans; D017730:Ki-1 Antigen / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011836:Radiation Tolerance; D015398:Signal Transduction; D037761:Sirtuins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*
chemical_list: D002843:Chromatin; D017730:Ki-1 Antigen; C501860:Sirt6 protein, mouse; D037761:Sirtuins