Work

Identification of a small molecule inhibitor of Sir2p

Year: 2001

Type: article

Abstract: 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 (HDA) 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.

Source: Proceedings of the National Academy of Sciences

DOI: 10.1073/pnas.261574398

Authors: Antonio Bedalov, Tonibelle Gatbonton, William P. Irvine, Daniel E. Gottschling, Julian A. Simon

Institution: Fred Hutch Cancer Center

Language: English

Topic: Sirtuins and Resveratrol in Medicine

Subfield: Geriatrics and Gerontology

Field: Medicine

Domain: Health Sciences

Open Access status: green

Funders: National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences

Awards: G4979657491, STRATEGIES FOR CONTEXT SPECIFIC ANTICANCER THERAPIES, Degradation-mediated nuclear protein quality control in yeast