The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases

Proc Natl Acad Sci U S A. 2000 May 23;97(11):5807-11. doi: 10.1073/pnas.110148297.

Abstract

Homologs of the chromatin-bound yeast silent information regulator 2 (SIR2) protein are found in organisms from all biological kingdoms. SIR2 itself was originally discovered to influence mating-type control in haploid cells by locus-specific transcriptional silencing. Since then, SIR2 and its homologs have been suggested to play additional roles in suppression of recombination, chromosomal stability, metabolic regulation, meiosis, and aging. Considering the far-ranging nature of these functions, a major experimental goal has been to understand the molecular mechanism(s) by which this family of proteins acts. We report here that members of the SIR2 family catalyze an NAD-nicotinamide exchange reaction that requires the presence of acetylated lysines such as those found in the N termini of histones. Significantly, these enzymes also catalyze histone deacetylation in a reaction that absolutely requires NAD, thereby distinguishing them from previously characterized deacetylases. The enzymes are active on histone substrates that have been acetylated by both chromatin assembly-linked and transcription-related acetyltransferases. Contrary to a recent report, we find no evidence that these proteins ADP-ribosylate histones. Discovery of an intrinsic deacetylation activity for the conserved SIR2 family provides a mechanism for modifying histones and other proteins to regulate transcription and diverse biological processes.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylation
  • Adenosine Diphosphate Ribose / metabolism
  • Animals
  • Chickens
  • Fungal Proteins / genetics
  • Fungal Proteins / physiology*
  • Gene Silencing / physiology*
  • Histone Deacetylases / genetics
  • Histone Deacetylases / physiology*
  • Histones / chemistry
  • Histones / metabolism*
  • Lysine / metabolism
  • Multigene Family
  • NAD / metabolism
  • Niacinamide / metabolism
  • Protein Processing, Post-Translational*
  • Recombinant Fusion Proteins / metabolism
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae / genetics
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae*
  • Sirtuin 2
  • Sirtuins
  • Trans-Activators / genetics
  • Trans-Activators / physiology*

Substances

  • Fungal Proteins
  • Histones
  • Recombinant Fusion Proteins
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae
  • Trans-Activators
  • NAD
  • Adenosine Diphosphate Ribose
  • Niacinamide
  • SIR2 protein, S cerevisiae
  • Sirtuin 2
  • Sirtuins
  • Histone Deacetylases
  • Lysine