Identification of a small molecule inhibitor of Sir2p

AUTOR(ES)

Bedalov, Antonio

FONTE

The National Academy of Sciences

RESUMO

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.

Documentos Relacionados

• Hyperactivation of the Silencing Proteins, Sir2p and Sir3p, Causes Chromosome Loss
• Sir2p exists in two nucleosome-binding complexes with distinct deacetylase activities
• The NAD+-dependent Sir2p histone deacetylase is a negative regulator of chromosomal DNA replication
• Sir2p suppresses recombination of replication forks stalled at the replication fork barrier of ribosomal DNA in Saccharomyces cerevisiae
• Discovery and functional characterization of a novel small molecule inhibitor of the intracellular phosphatase, SHIP2