title: Assembly of the SIR complex and its regulation by O-acetyl-ADP-ribose, a product of NAD-dependent histone deacetylation.
abstract: Assembly of silent chromatin domains in budding yeast involves the deacetylation of histone tails by Sir2 and the association of the Sir3 and Sir4 proteins with hypoacetylated histone tails. Sir2 couples deacetylation to NAD hydrolysis and the synthesis of a metabolite, O-acetyl-ADP-ribose (AAR), but the functional significance of NAD hydrolysis or AAR, if any, is unknown. Here we examine the association of the Sir2, Sir3, and Sir4 proteins with each other and histone tails. Our analysis reveals that deacetylation of histone H4-lysine 16 (K16), which is critical for silencing in vivo, is also critical for the binding of Sir3 and Sir4 to histone H4 peptides in vitro. Moreover, AAR itself promotes the association of multiple copies of Sir3 with Sir2/Sir4 and induces a dramatic structural rearrangement in the SIR complex. These results suggest that Sir2 activity modulates the assembly of the SIR complex through both histone deacetylation and AAR synthesis.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Gunn-Guang
authors.initials: GG
authors.lastname: Liou
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Tanny
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Kruger
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Thomas
authors.initials: T
authors.lastname: Walz
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115. Electronic address: danesh@hms.harvard.edu.
authors.forename: Danesh
authors.initials: D
authors.lastname: Moazed
mesh_terms: D001665:Binding Sites / Q000502:physiology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D046911:Macromolecular Substances / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D038961:O-Acetyl-ADP-Ribose / Q000096:biosynthesis / Q000378:metabolism*; D050543:Phosphoglycerate Dehydrogenase; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D056565:Sirtuin 2; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; D046911:Macromolecular Substances; D038961:O-Acetyl-ADP-Ribose; C061573:SIR4 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; D009243:NAD; D050543:Phosphoglycerate Dehydrogenase; C493278:SER3 protein, S cerevisiae; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2; D037761:Sirtuins; D006655:Histone Deacetylases; D008239:Lysine