Sirt6 is a protein that in humans is encoded by the SIRT6 gene. It is a member of the sirtuin family of proteins, which are homologs to the Sir2 protein in yeast. Sirt6 has been shown to possess mono-ADP-ribosyltransferase activity and to deacetylate histone H3 lysine 9 (H3K9) and lysine 56 (H3K56). These activities suggest that Sirt6 may play a role in chromatin remodeling, gene silencing, and DNA repair. In addition, Sirt6 deficient mice exhibit increased genomic instability and accelerated aging.
The sirtuin family of proteins are nicotinamide adenine dinucleotide (NAD+)-dependent enzymes that catalyze the removal of acetyl groups from proteins. The first sirtuin was discovered in yeast, where it was shown to be required for silencing of mating-type loci during cell growth in glucose-limited conditions. Since then, seven additional mammalian sirtuins have been identified: SIRT1-7. All sirtuins share a common NAD+ binding domain and catalytic domain, but differ in their substrate specificity and tissue distribution.
SIRT6 was first identified as a negative regulator of p53 activity through its ability to deacetylate p53 at lysine 310 (p53K310). This deacetylation leads to the inhibition of p53-mediated transcriptional activation and cell cycle arrest. Subsequent studies have demonstrated that SIRT6 also regulates other key cellular processes including inflammation, metabolism, stress resistance, DNA repair, and telomere maintenance. For example, SIRT6 has been shown to inhibit NF-κB signaling by directly deacetylating Lys310 on RelA/p65 subunit of NF-κB complex Furthermore, mouse embryonic fibroblasts lacking SIRT6 show increased sensitivity to UV radiation due to impaired DNA double strand break repair Additionally, both human cells and mouse models lacking SIRT6 display shortened telomeres Taken together these findings suggest that loss of SIRT6 function contributes to premature aging phenotypes via multiple mechanisms .