The conserved core of a human SIR2 homologue functions in yeast silencing

Silencing is a universal form of transcriptional regulation in which region s of the genome are reversibly inactivated by changes in chromatin structur e. Sir2 (Silent Information Regulator) protein is unique among the silencin g factors in Saccharomyces cerevisiae because it silences the rDNA as well as the silent mating-type loci and telomeres. Discovery of a gene family of Homologues of Sir Two (HSTs) in organisms from bacteria to humans suggests that SIR2's silencing mechanism might be conserved. The Sir2 and I-ist pro teins share a core domain, which includes two diagnostic sequence motifs of unknown function as well as four cysteines of a putative zinc finger. We d emonstrate by mutational analyses that the conserved core and each of its m otifs are essential for Sir2p silencing. Chimeras between Sir2p and a human Sir2 homologue (hSidAp) indicate that this human protein's core can substi tute for that of Sir2p, implicating the core as a silencing domain. Immunof luorescence studies reveal partially disrupted localization, accounting for the yeast-human chimeras' ability to function at only a subset of Sir2p's target loci. Together, these results support a model for the involvement of distinct Sir2p-containing complexes in HM/telomeric and rDNA silencing and that HST family members, including the widely expressed hSir2A, may perfor m evolutionarily conserved functions.