Histone H3 specific acetyltransferases are essential for cell cycle progression
- LeAnn Howe1,
- Darryl Auston2,
- Patrick Grant3,
- Sam John1,5,
- Richard G. Cook4,
- Jerry L. Workman1, and
- Lorraine Pillus2,6
- 1Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA; 2Division of Biology, University of California, San Diego, California 92093, USA; 3Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia 22908, USA; 4Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA
Abstract
Longstanding observations suggest that acetylation and/or amino-terminal tail structure of histones H3 and H4 are critical for eukaryotic cells. For Saccharomyces cerevisiae, loss of a single H4-specific histone acetyltransferase (HAT), Esa1p, results in cell cycle defects and death. In contrast, although several yeast HAT complexes preferentially acetylate histone H3, the catalytic subunits of these complexes are not essential for viability. To resolve the apparent paradox between the significance of H3 versus H4 acetylation, 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. Simultaneous disruption of SAS3, the homolog of the MOZ leukemia gene, and GCN5, the hGCN5/PCAFhomolog, is synthetically lethal due to loss of acetyltransferase activity. This key combination of activities is specific for these 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 acetylation and arrest in the G2/M phase of the cell cycle. The strikingly similar effect of loss of combined essential H3 HAT activities and the loss of a single essential H4 HAT underscores the fundamental biological significance of each of these chromatin-modifying activities.
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Footnotes
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↵5 Present address: Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Bethesda, Maryland 20892, USA.
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↵6 Corresponding author.
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E-MAIL lpillus{at}biomail.ucsd.edu; FAX (858) 534-0555.
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Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.931401.
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- Received July 26, 2001.
- Accepted October 12, 2001.
- Cold Spring Harbor Laboratory Press
