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

Genomic Instability and Aging-Like Phenotype in the Absence of Mammalian SIRT6

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Genomic Instability and Aging-Like Phenotype in the Absence of Mammalian SIRT6

Raul Mostoslavsky et al. Cell. .

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.

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