Assembly of the SIR complex and its regulation by O-acetyl-ADP-ribose, a product of NAD-dependent histone deacetylation

Cell. 2005 May 20;121(4):515-527. doi: 10.1016/j.cell.2005.03.035.

Authors

Gunn-Guang Liou¹, Jason C Tanny¹, Ryan G Kruger², Thomas Walz¹, Danesh Moazed³

Affiliations

¹ Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
² Department of Biochemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
³ Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115. Electronic address: danesh@hms.harvard.edu.

PMID: 15907466
DOI: 10.1016/j.cell.2005.03.035

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Binding Sites / physiology
Histone Deacetylases / genetics
Histone Deacetylases / metabolism*
Histones / metabolism*
Lysine / metabolism
Macromolecular Substances / metabolism
NAD / metabolism*
O-Acetyl-ADP-Ribose / biosynthesis
O-Acetyl-ADP-Ribose / metabolism*
Phosphoglycerate Dehydrogenase
Protein Binding / physiology
Protein Structure, Tertiary / physiology
Saccharomyces cerevisiae / genetics
Saccharomyces cerevisiae / metabolism
Saccharomyces cerevisiae Proteins / genetics
Saccharomyces cerevisiae Proteins / metabolism
Silent Information Regulator Proteins, Saccharomyces cerevisiae / genetics
Silent Information Regulator Proteins, Saccharomyces cerevisiae / metabolism*
Sirtuin 2
Sirtuins / genetics
Sirtuins / metabolism

Substances

Histones
Macromolecular Substances
O-Acetyl-ADP-Ribose
SIR4 protein, S cerevisiae
Saccharomyces cerevisiae Proteins
Silent Information Regulator Proteins, Saccharomyces cerevisiae
NAD
Phosphoglycerate Dehydrogenase
SER3 protein, S cerevisiae
SIR2 protein, S cerevisiae
Sirtuin 2
Sirtuins
Histone Deacetylases
Lysine