Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase

Yeast Sir2 is a heterochromatin component that silences transcription at si lent mating loci(1), telomeres(2) and the ribosomal DNA(3,4), and that also suppresses recombination in the rDNA(5) and extends replicative life span( 6). Mutational studies indicate that lysine 16 in the amino-terminal tail o f histone H4 and lysines 9, 14 and 18 in H3 are critically important in sil encing, whereas lysines 5, 8 and 12 of H4 have more redundant functions(7-9 ). Lysines 9 and 14 of histone H3 and lysines 5, 8 and 16 of H4 are acetyla ted in active chromatin and hypoacetylated in silenced chromatin, and overe xpression of Sir2 promotes global deacetylation of histones(9,10), indicati ng that Sir2. may be a histone deacetylase. Deacetylation of lysine 16 of H 4 is necessary for binding the silencing protein, Sir3 (ref. 8). Here we sh ow that yeast and mouse Sir2 proteins are nicotinamide adenine dinucleotide (NAD)dependent histone deacetylases, which deacetylate lysines 9 and 14 of H3 and specifically lysine 16 of H4. Our analysis of two SIR2 mutations su pports the idea that this deacetylase activity accounts for silencing, reco mbination suppression and extension of life span in vivo. These findings pr ovide a molecular framework of NAD-dependent histone deacetylation that con nects metabolism, genomic silencing and ageing in yeast and, perhaps, in hi gher eukaryotes.