The article discusses the molecular mechanisms of the SIR2 family proteins, which are NAD-dependent protein deacetylases found in various organisms. These proteins, including yeast SIR2 and its homologs, play crucial roles in transcriptional silencing, recombination suppression, chromosomal stability, metabolic regulation, meiosis, and aging. The study reveals that SIR2 family members catalyze an NAD-nicotinamide exchange reaction that requires acetylated lysines, such as those found in histone N-termini. Additionally, these enzymes can deacetylate histones in a reaction that absolutely depends on NAD, distinguishing them from previously characterized deacetylases. The authors provide evidence that these proteins do not ADP-ribosylate histones, contrary to recent reports. The findings suggest that the SIR2 family proteins modify histones and other proteins to regulate transcription and diverse biological processes. The study also explores the potential roles of these proteins in various cellular functions and their implications in diseases.The article discusses the molecular mechanisms of the SIR2 family proteins, which are NAD-dependent protein deacetylases found in various organisms. These proteins, including yeast SIR2 and its homologs, play crucial roles in transcriptional silencing, recombination suppression, chromosomal stability, metabolic regulation, meiosis, and aging. The study reveals that SIR2 family members catalyze an NAD-nicotinamide exchange reaction that requires acetylated lysines, such as those found in histone N-termini. Additionally, these enzymes can deacetylate histones in a reaction that absolutely depends on NAD, distinguishing them from previously characterized deacetylases. The authors provide evidence that these proteins do not ADP-ribosylate histones, contrary to recent reports. The findings suggest that the SIR2 family proteins modify histones and other proteins to regulate transcription and diverse biological processes. The study also explores the potential roles of these proteins in various cellular functions and their implications in diseases.