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 FrendeweyWojtek 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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)315-329
Number of pages15
JournalCell
Volume124
Issue number2
DOIs
StatePublished - Jan 27 2006

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Mostoslavsky, R., Chua, K. F., Lombard, D. B., Pang, W. W., Fischer, M. R., Gellon, L., Liu, P., Mostoslavsky, G., Franco, S., Murphy, M. M., Mills, K. D., Patel, P., Hsu, J. T., Hong, A. L., Ford, E., Cheng, H. L., Kennedy, C., Nunez, N., Bronson, R., ... Alt, F. W. (2006). Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell, 124(2), 315-329. https://doi.org/10.1016/j.cell.2005.11.044