The Silent Information Regulator (Sir2) family of genes is a highly conserved group of genes that encode nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylases, also known as class III histone deacetylases. The first discovered and best characterized of this family is Saccharomyces cerevisiae Sir2, which is involved in silencing of mating type loci, telomere maintenance, DNA damage response, and cell aging. SirT6, a mammalian homolog of Sir2, is a nuclear, chromatin-associated protein that promotes the normal maintenance of genome integrity mediated by the base excision repair (BER) pathway. The BER pathway repairs single-stranded DNA lesions that arise spontaneously from endogenous alkylation, oxidation, and deamination events. SirT6 deficient mice show increased sensitivity to DNA-damaging agents, including the alkylating agents MMS and H2O2. In addition, these mice show genome instability with increased frequency of fragmented chromosomes, detached centromeres, and gaps. SirT6 may regulate the BER pathway by deacetylating DNA Polβ or other core components of the pathway.