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Genomic instability and aging-like phenotype in the absence of mammalian SIRT6.

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.

Pubmed ID: 16439206

Authors

  • Mostoslavsky R
  • Chua KF
  • Lombard DB
  • Pang WW
  • Fischer MR
  • Gellon L
  • Liu P
  • Mostoslavsky G
  • Franco S
  • Murphy MM
  • Mills KD
  • Patel P
  • Hsu JT
  • Hong AL
  • Ford E
  • Cheng HL
  • Kennedy C
  • Nunez N
  • Bronson R
  • Frendewey D
  • Auerbach W
  • Valenzuela D
  • Karow M
  • Hottiger MO
  • Hursting S
  • Barrett JC
  • Guarente L
  • Mulligan R
  • Demple B
  • Yancopoulos GD
  • Alt FW

Journal

Cell

Publication Data

January 27, 2006

Associated Grants

  • Agency: PHS HHS, Id: K08
  • Agency: NIDDK NIH HHS, Id: R01 DK088190

Mesh Terms

  • Aging
  • Animals
  • Antigens, CD30
  • Cell Proliferation
  • Chromatin
  • DNA Damage
  • DNA Repair
  • Genetic Diseases, Inborn
  • Genomic Instability
  • Humans
  • Lymphocytes
  • Mice
  • Mice, Knockout
  • Phenotype
  • Radiation Tolerance
  • Signal Transduction
  • Sirtuins