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

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

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.

Keywords: Aging/*metabolism; Animals; Antigens, CD30/metabolism; Cell Proliferation; Chromatin/metabolism; DNA Damage; DNA Repair; Genetic Diseases, Inborn/*genetics/pathology; *Genomic Instability; Humans; Lymphocytes/immunology; Mice; Mice, Knockout; Phenotype; Radiation Tolerance; Signal Transduction; Sirtuins/deficiency/*genetics/*physiology
Journal: Cell
Volume: 124
Issue: 2
Pages: 315-29
Date: Jan. 28, 2006
PMID: 16439206
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Citation:

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 (2006) Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124: 315-29.


Lifespan Factors:
  • Sirt6 sirtuin 6 (silent mating type information regulation 2, homolog) 6 (S. cerevisiae)


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