Chromatin regulation and genome maintenance by mammalian SIRT6

Saccharomyces cerevisiae Sir2 is an NAD(+)-dependent histone deacetylase that links chromatin silencing to genomic stability, cellular metabolism and lifespan regulation. In mice, deficiency for the Sir2 family member SIRT6 leads to genomic instability, metabolic defects and degenerative pathologies associated with aging. Until recently, SIRT6 was an orphan enzyme whose catalytic activity and substrates were unclear. However, new mechanistic insights have come from the discovery that SIRT6 is a highly substrate-specific histone deacetylase that promotes proper chromatin function in several physiologic contexts, including telomere and genome stabilization, gene expression and DNA repair. By maintaining both the integrity and the expression of the mammalian genome, SIRT6 thus serves several roles that parallel Sir2 function. In this article, we review recent advances in understanding the mechanisms of SIRT6 action and their implications for human biology and disease.