Histone H3 specific acetyltransferases are essential for cell cycle progression

Longstanding, observations suggest that acetylation and/or amino-terminal t ail structure of histones H3 and H4 are critical for eukaryotic cells. For Saccharomyces cerevisiae, loss of a single H4-specific histone acetyltransf erase (HAT), Esa1p, results in cell cycle defects and death. In contrast, a lthough several yeast HAT complexes preferentially acetylate histone H3, th e catalytic subunits of these complexes are not essential for viability. To resolve the apparent paradox between the significance of H3 versus H4 acet ylation, we tested the hypothesis that H3 modification is essential, but is accomplished through combined activities of two enzymes. We observed that Sas3p and Gcn5p HAT complexes have overlapping patterns of acetylation. Sim ultaneous disruption of SAS3, the homolog of the MOZ leukemia gene, and GCN 5, the hGCN5/PCAF homolog, is, synthetically lethal due to loss of acetyltr ansferase activity. This key combination of activities is specific for thes e two HATS because neither is, synthetically lethal with mutations of other MYST family or H3-specific acetyltransferases. Further, the combined loss of GCN5 and SAS3 functions results in an extensive, global loss of H3 acety lation and arrest in the G(2)/M phase of the cell cycle. The strikingly sim ilar effect of loss of combined essential H3 HAT activities and the loss of a single essential H4 RAT underscores the fundamental biological significa nce of each of these chromatin-modifying activities.