Genomic instability and aging-like phenotype in the absence of mammalian SIRT6 |
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| Authors: | Mostoslavsky Raul Chua Katrin F Lombard David B Pang Wendy W Fischer Miriam R Gellon Lionel Liu Pingfang Mostoslavsky Gustavo Franco Sonia Murphy Michael M Mills Kevin D Patel Parin Hsu Joyce T Hong Andrew L Ford Ethan Cheng Hwei-Ling Kennedy Caitlin Nunez Nomeli Bronson Roderick Frendewey David Auerbach Wojtek Valenzuela David Karow Margaret Hottiger Michael O Hursting Stephen Barrett J Carl Guarente Leonard Mulligan Richard Demple Bruce Yancopoulos George D Alt Frederick W |
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| Affiliation: | Howard Hughes Medical Institute, The Children's Hospital, CBR Institute for Biomedical Research, Harvard University Medical School, Boston, MA 02115, USA. |
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| 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. |
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