Sir2 is a conserved protein and was recently shown to regulate lifespan extension both in budding yeast and nematode. In 2000, it was reported that the yeast Sir2 protein is a NAD(+)-dependent histone deacetylase that plays a critical role in transcriptional silencing, genome stability and longevity. In mammals, the homologs of Sir2 have been named Sirtuins (SIRTs), with seven members in a family termed SIRT1 through SIRT7. They share a conserved central deacetylase domain but have different N- and C termini and display distinct subcellular localization, suggesting different biological functions (1).
The distant mammalian Sir2 homolog SIRT6 is a broadly expressed, predominantly nuclear protein (2) like SIRT1. Inactivation of the Sirt6 gene in mice leads to dramatically shortened life span and a premature aging-like phenotype (3). It was shown that SIRT6 is a histone H3 lysine 9 deacetylase, and identified a role for SIRT6 activity at telomeric chromatin, where it prevents telomere dysfunction in human cells (4). In addition, SIRT6 also deacetylates histone H3 acetylated lysine 56 in vivo to promote genomic stability (5). In term of function, SIRT6 binds to the NF-κB subunit RELA and attenuates NF-κB signaling by modifying chromatin at NF-κB target genes (6). Thus SIRT6-mediated control of NF-κB prevents aging-associated, hyperactive NF-κB-dependent gene expression, and inhibition of NF-κB can rescue the early lethality of Sirt6 knockout mice. Overexpression of wild-type Sirt6, but not the catalytically inactive form, consistently resulted in increased tumor necrosis factor protein production relative to its mRNA levels (7).