Author/Authors :
Guarente، Leonard نويسنده , , Lombard، David B. نويسنده , , Chua، Katrin F. نويسنده , , Mostoslavsky، Raul نويسنده , , Franco، Sonia نويسنده , , Alt، Frederick W. نويسنده , , Bronson، Roderick T. نويسنده , , Pang، Wendy W. نويسنده , , Fischer، Miriam R. نويسنده , , Gellon، Lionel نويسنده , , Liu، Pingfang نويسنده , , Mostoslavsky، Gustavo نويسنده , , Murphy، Michael M. نويسنده , , Mills، Kevin D. نويسنده , , Patel، Parin نويسنده , , Hsu، Joyce T. نويسنده , , Hong، Andrew L. نويسنده , , Ford، Ethan نويسنده , , Cheng، Hwei-Ling نويسنده , , Kennedy، Caitlin نويسنده , , Nunez، Nomeli نويسنده , , Frendewey، David نويسنده , , Auerbach، Wojtek نويسنده , , Valenzuela، David نويسنده , , Karow، Margaret نويسنده , , Hottiger، Michael O. نويسنده , , Hursting، Stephen نويسنده , , Barrett، J. Carl نويسنده , , Mulligan، Richard نويسنده , , Demple، Bruce نويسنده , , Yancopoulos، George D. نويسنده ,
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.
