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

Cell. 2006 Jan 27;124(2):315-29. doi: 10.1016/j.cell.2005.11.044.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism*
  • Animals
  • Cell Proliferation
  • Chromatin / metabolism
  • DNA Damage
  • DNA Repair
  • Genetic Diseases, Inborn / genetics*
  • Genetic Diseases, Inborn / pathology
  • Genomic Instability*
  • Humans
  • Ki-1 Antigen / metabolism
  • Lymphocytes / immunology
  • Mice
  • Mice, Knockout
  • Phenotype
  • Radiation Tolerance
  • Signal Transduction
  • Sirtuins / deficiency
  • Sirtuins / genetics*
  • Sirtuins / physiology*

Substances

  • Chromatin
  • Ki-1 Antigen
  • Sirt6 protein, mouse
  • Sirtuins