Authors:
Tiara L.A. Kawahara, Eriko Michishita, Adam S. Adler, Mara Damian, Elisabeth Berber, Meihong Lin, Ron A. McCord, Kristine C.L. Ongaigui, Lisa D. Boxer, Howard Y. Chang, and Katrin F. Chua
Summary:
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- B signaling. SIRT6 interacts with the NF- B RELA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF- 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- B-dependent modulation of gene expression, apoptosis, and cellular senescence. Computational genomics analyses revealed increased activity of NF- 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- B signaling via H3K9 deacetylation at chromatin, and hyperactive NF- B signaling may contribute to premature and normal aging.
Source:
Cell; Vol. 136, Issue 1, 62-74 (01/09/09)