Silencing is an epigenetic form of transcriptional regulation whereby genes are heritably, but not necessarily permanently, inactivated. We have identified the Saccharomyces cerevisiae genes SAS2 and SAS3 through a screen for enhancers of sir1 epigenetic silencing defects. SAS2, SAS3 and a Schizosaccharomyces pombe homologue are closely related to several human genes, including one associated with acute myeloid leukaemia arising from the recurrent translocation t(8;16)(p11;p13) and one implicated in HIV–1 Tat interactions. All of these genes encode proteins with an atypical zinc finger and well–conserved similarities to acetyltransferases. Sequence similarities and yeast mutant phenotypes suggest that SAS–like genes function in transcriptional regulation and cell–cycle exit and reveal novel connections between transcriptional silencing and human disease.