Sirtuin 6 (SIRT6) is a nuclear NAD+-dependent deacetylase of histone H3 that regulates genome stability and gene expression. However, nonhistone substrates and additional catalytic activities of SIRT6, including long-chain deacylation and mono-ADP-ribosylation of other proteins, have also been reported, but many of these noncanonical roles remain enigmatic. Genetic studies have revealed critical homeostatic cellular functions of SIRT6, underscoring the need to better understand which catalytic functions and molecular pathways are driving SIRT6-associated phenotypes.
