Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 98, Issue 26, Pages 15113-15118Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.261574398
Keywords
chemical genetics; histone deacetylase; silencing; SIR2
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Funding
- NCI NIH HHS [CA78746] Funding Source: Medline
- NHLBI NIH HHS [HL04211] Funding Source: Medline
- NIGMS NIH HHS [GM43893, R01 GM043893] Funding Source: Medline
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Sir2p is an NAD(+)-dependent histone deacetylase required for chromatin-dependent silencing in yeast. In a cell-based screen for inhibitors of Sir2p, we identified a compound, splitomicin, that creates a conditional phenocopy of a sir2 deletion mutant in Saccharomyces cerevisiae. Cells grown in the presence of the drug have silencing defects at telomeres, silent mating-type loci, and the ribosomal DNA. In addition, whole genome microarray experiments show that splitomicin selectively inhibits Sir2p. In vitro, splitomicin inhibits NAD+-dependent histone deacetylase activity (HIDA) of the Sir2 protein. Mutations in SIR2 that confer resistance to the drug map to the likely acetylated histone tail binding domain of the protein. By using splitomicin as a chemical genetic probe, we demonstrate that continuous HDA of Sir2p is required for maintaining a silenced state in nondividing cells.
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