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 RIS Download
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