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SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span.

Cell | Jan 9, 2009

http://www.ncbi.nlm.nih.gov/pubmed/19135889

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-kappaB signaling. SIRT6 interacts with the NF-kappaB RELA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF-kappaB target gene promoters. In SIRT6-deficient cells, hyperacetylation of H3K9 at these target promoters is associated with increased RELA promoter occupancy and enhanced NF-kappaB-dependent modulation of gene expression, apoptosis, and cellular senescence. Computational genomics analyses revealed increased activity of NF-kappaB-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-kappaB signaling via H3K9 deacetylation at chromatin, and hyperactive NF-kappaB signaling may contribute to premature and normal aging.

Pubmed ID: 19135889 RIS Download

Mesh terms: Acetylation | Animals | Cell Line | Chromatin | Crosses, Genetic | Embryo, Mammalian | Gene Expression Regulation, Developmental | Humans | Longevity | Mice | NF-kappa B | Promoter Regions, Genetic | Sirtuins | Transcription Factor RelA

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Associated grants

  • Agency: NIA NIH HHS, Id: K08 AG028961
  • Agency: NIA NIH HHS, Id: K08 AG028961-03
  • Agency: NIA NIH HHS, Id: R01 AG028867
  • Agency: NIA NIH HHS, Id: R01 AG028867-04
  • Agency: NCI NIH HHS, Id: R01 CA118750
  • Agency: NCI NIH HHS, Id: R01 CA118750-02
  • Agency: NCI NIH HHS, Id: R01 CA118750-03

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