期刊
CELL
卷 136, 期 1, 页码 62-74出版社
CELL PRESS
DOI: 10.1016/j.cell.2008.10.052
关键词
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资金
- NIH
- Department of Veterans Affairs Merit Review
- Stanford Graduate Fellowship
- California Breast Cancer Research Program
- American Cancer Society
- Damon Runyon Cancer Research Foundation
- Paul B. Beeson Aging Research Program
Members of the sirtuin (SIRT) family of NAD-dependent deacetylases promote longevity in multiple organisms. Deficiency of mammalian SIRT6 leads to shortened life span and an aging-like phenotype in mice, but the underlying molecular mechanisms are unclear. Here we show that SIRT6 functions at chromatin to attenuate NF-kappa B signaling. SIRT6 interacts with the NF-kappa B RELA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF-kappa B target gene promoters. In SIRT6-deficient cells, hyperacetylation of H3K9 at these target promoters is associated with increased RELA promoter occupancy and enhanced NF-kappa B-dependent modulation of gene expression, apoptosis, and cellular senescence. Computational genomics analyses revealed increased activity of NF-kappa B-driven gene expression programs in multiple Sirt6-deficient tissues in vivo. Moreover, haploinsufficiency of RelA rescues the early lethality and degenerative syndrome of Sirt6-deficient mice. We propose that SIRT6 attenuates NF-kappa B signaling via H3K9 deacetylation at chromatin, and hyperactive NF-kappa B signaling may contribute to premature and normal aging.
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