A phylogenetically conserved NAD(+)-dependent protein deacetylase activityin the Sir2 protein family

The yeast Sir2 protein, required for transcriptional silencing, has an NAD( +)-dependent histone deacetylase (HDA) activity. Yeast extracts contain a N AD(+)-dependent HDA activity that is eliminated in a yeast strain from whic h SIR2 and its four homologs have been deleted. This HDA activity is also d isplayed by purified yeast Sir2p and homologous Archaeal, eubacterial, and human proteins, and depends completely on NAD(+) in all species tested. The yeast NPT1 gene, encoding an important NAD(+) synthesis enzyme, is require d for rDNA and telomeric silencing and contributes to silencing of the HM l oci. Null mutants in this gene have significantly reduced intracellular NAD (+) concentrations and have phenotypes similar to sir2 null mutants. Surpri singly, yeast from which all five SIR2 homologs have been deleted have rela tively normal bulk histone acetylation levels. The evolutionary conservatio n of this regulated activity suggests that the Sir2 protein family represen ts a set of effector proteins in an evolutionarily conserved signal transdu ction pathway that monitors cellular energy and redox states.