SIR2 and its homologs are NAD-dependent protein deacetylases. The yeast SIR2 protein is involved in transcriptional silencing of silent mating loci, telomeres, and rDNA. It forms complexes with SIR3 and SIR4 at silent mating loci and telomeres, and with other proteins at rDNA. SIR2 homologs are found in all biological kingdoms, including archaeabacteria, eubacteria, and mammals. The SIR2 family's functions include transcriptional silencing, suppression of recombination, chromosomal stability, metabolic regulation, meiosis, and aging. The study shows that SIR2 family members catalyze an NAD-nicotinamide exchange reaction that requires acetylated lysines, such as those found in histone N termini. These enzymes also catalyze histone deacetylation in a reaction that absolutely requires NAD, distinguishing them from previously characterized deacetylases. The study found no evidence that these proteins ADP-ribosylate histones, contrary to a recent report. The SIR2 family's intrinsic deacetylation activity provides a mechanism for modifying histones and other proteins to regulate transcription and biological processes. The study also shows that SIR2 can deacetylate histones acetylated by HAT1 or ESA1, and that this deacetylation is dependent on NAD. The study highlights the importance of understanding the molecular mechanisms of SIR2 family proteins in regulating chromatin structure and biological processes. The study also discusses the potential roles of SIR2 homologs in other organisms, including their possible involvement in processes such as suppression of recombination, maintenance of genome stability, and transcriptional regulation. The study concludes that understanding the unique mechanism and targets of these NAD-dependent deacetylase activities will be critical for future studies.SIR2 and its homologs are NAD-dependent protein deacetylases. The yeast SIR2 protein is involved in transcriptional silencing of silent mating loci, telomeres, and rDNA. It forms complexes with SIR3 and SIR4 at silent mating loci and telomeres, and with other proteins at rDNA. SIR2 homologs are found in all biological kingdoms, including archaeabacteria, eubacteria, and mammals. The SIR2 family's functions include transcriptional silencing, suppression of recombination, chromosomal stability, metabolic regulation, meiosis, and aging. The study shows that SIR2 family members catalyze an NAD-nicotinamide exchange reaction that requires acetylated lysines, such as those found in histone N termini. These enzymes also catalyze histone deacetylation in a reaction that absolutely requires NAD, distinguishing them from previously characterized deacetylases. The study found no evidence that these proteins ADP-ribosylate histones, contrary to a recent report. The SIR2 family's intrinsic deacetylation activity provides a mechanism for modifying histones and other proteins to regulate transcription and biological processes. The study also shows that SIR2 can deacetylate histones acetylated by HAT1 or ESA1, and that this deacetylation is dependent on NAD. The study highlights the importance of understanding the molecular mechanisms of SIR2 family proteins in regulating chromatin structure and biological processes. The study also discusses the potential roles of SIR2 homologs in other organisms, including their possible involvement in processes such as suppression of recombination, maintenance of genome stability, and transcriptional regulation. The study concludes that understanding the unique mechanism and targets of these NAD-dependent deacetylase activities will be critical for future studies.