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

Document Type


Publication Date



Animals, Antigens-CD30, Cell-Proliferation, Chromatin, DNA-Damage, DNA-Repair, Genetic-Diseases-Inborn, Genomic-Instability, Humans, Lymphocytes, Mice, Mice-Knockout, Phenotype, Radiation-Tolerance, Research-Support-N, I, H, -Extramural, Research-Support-Non-U, S, -Gov't, Signal-Transduction, Sirtuins

JAX Source

Cell 2006 Jan; 124(2):315-29.


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.