Genomic instability and aging-like phenotype in the absence of mammalian SIRT6
Raul Mostoslavsky, Katrin F Chua, David B Lombard, Wendy W Pang, Miriam R Fischer, Lionel Gellon, Pingfang Liu, Gustavo Mostoslavsky, Sonia Franco, Michael M Murphy, Kevin D Mills, Parin Patel, Joyce T Hsu, Andrew L Hong, Ethan Ford, Hwei-Ling Cheng, Caitlin Kennedy, Nomeli Nunez, Roderick Bronson, David Frendewey, Wojtek Auerbach, David Valenzuela, Margaret Karow, Michael O Hottiger, Stephen Hursting, J Carl Barrett, Leonard Guarente, Richard Mulligan, Bruce Demple, George D Yancopoulos, Frederick W Alt, Raul Mostoslavsky, Katrin F Chua, David B Lombard, Wendy W Pang, Miriam R Fischer, Lionel Gellon, Pingfang Liu, Gustavo Mostoslavsky, Sonia Franco, Michael M Murphy, Kevin D Mills, Parin Patel, Joyce T Hsu, Andrew L Hong, Ethan Ford, Hwei-Ling Cheng, Caitlin Kennedy, Nomeli Nunez, Roderick Bronson, David Frendewey, Wojtek Auerbach, David Valenzuela, Margaret Karow, Michael O Hottiger, Stephen Hursting, J Carl Barrett, Leonard Guarente, Richard Mulligan, Bruce Demple, George D Yancopoulos, Frederick W Alt
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.
Source: PubMed