Sir inhibitor

Sir2p is an NAD-dependent histone deacetylase that is involved in chromatin silencing. In the December 18 Proceedings of the National Academy of Sciences, Antonio Bedalov and colleagues at the Fred Hutchinson Cancer Research Center describe the isolation of splitomicin, an inhibitor of Sir2p activity (Proc Natl Acad Sci USA 2001, 98:15113-15118). They performed a genetic screen for compounds that inhibit silencing of telomeric or mating-type loci in yeast. This led them to a compound, 1,2-dihydro-3H-naptho[2,1b]pyran-3-one, which they named splitomicin; it phenocopies sir2 mutation by inhibiting histone deacetylase activity. Whole-genome microarray analysis confirmed that splitomicin affects genes silenced by Sir2p. Bedalov et al.used splitomicin to demonstrate that Sir2p histone deacetylase activity is required to maintain the silenced state in non-dividing cells.