A cytosolic NAD-dependent deacetylase, Hst2p, can modulate nucleolar and telomeric silencing in yeast

In budding yeast, the silent information regulator Sir2p is a nuclear NAD-d ependent deacetylase that is essential for both telomeric and rDNA silencin g. All eukaryotic species examined to date have multiple homologues of Sir two (HSTs), which share a highly conserved globular core domain. Here we re port that yeast Hst2p and a mammalian Hst2p homologue, hSirT2p, are cytopla smic in yeast and human cells, in contrast to yHst1p and ySir2p which are e xclusively nuclear. Although yHst2p cannot restore silencing in a sir2 dele tion, overexpression of yHst2p influences nuclear silencing events in a SIR 2 strain, derepressing subtelomeric silencing while increasing repression i n the rDNA. In contrast, a form of ySir2p carrying a point mutation in the conserved core domain disrupts both telomeric position effect (TPE) and rDN A repression at low expression levels, This argues that nonnuclear yHst2p c an compete for a substrate or ligand specifically required for telomeric, a nd not rDNA repression.