The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases.
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.
Landry
J
J
Department of Biochemistry and Cell Biology, State University of New York, Stony Brook, NY 11794-5215, USA.
Sutton
A
A
Tafrov
S T
ST
Heller
R C
RC
Stebbins
J
J
Pillus
L
L
Sternglanz
R
R
D000107:Acetylation; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000818:Animals; D002645:Chickens; D005656:Fungal Proteins / Q000235:genetics / Q000502:physiology*; D020868:Gene Silencing / Q000502:physiology*; D006655:Histone Deacetylases / Q000235:genetics / Q000502:physiology*; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D005810:Multigene Family; D009243:NAD / Q000378:metabolism; D009536:Niacinamide / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; D056565:Sirtuin 2; D037761:Sirtuins; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*
D005656:Fungal Proteins; D006657:Histones; D011993:Recombinant Fusion Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; D015534:Trans-Activators; D009243:NAD; D000246:Adenosine Diphosphate Ribose; D009536:Niacinamide; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2; D037761:Sirtuins; D006655:Histone Deacetylases; D008239:Lysine