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, and Frederick W. Alt

Howard Hughes Medical Institute, The Children's Hospital, CBR Institute for Biomedical Research, Harvard University Medical School, Boston, MA 02115, USA
Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, 8057 Zurich, Switzerland

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.