MCB Accepts, published online ahead of print on 22 January 2008

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Mol. Cell. Biol. doi:10.1128/MCB.01653-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Functional dissection of the NuA4 histone acetyltransferase reveals its role as a genetic hub and that Eaf1 is essential for complex integrity

Leslie Mitchell, Jean-Philippe Lambert, Maria Gerdes, Ashraf S. Al-Madhoun, Ilona S. Skerjanc, Daniel Figeys, and Kristin Baetz^*

Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario K1H 8M5; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5

^* To whom correspondence should be addressed. Email: kbaetz{at}uottawa.ca.

The Saccharomyces cerevisiae NuA4 histone acetyltransferase complex catalyzes the acetylation of histone H4, and the histone variant Htz1 to regulate key cellular events including transcription, DNA repair, and faithful chromosome segregation. To further investigate the cellular processes impacted by NuA4, we exploited the non-essential subunits of the complex to build an extensive NuA4 genetic interaction network map. The map reveals that NuA4 is a genetic hub whose function buffers a diverse range of cellular processes, many not previously linked to the complex, including Golgi-vacuole vesicle-mediated transport. Further, we probe the role that non-essential subunits play in NuA4 complex integrity. We find that most non-essential subunits have little impact on NuA4 complex integrity and display between 12-42 genetic interactions. In contrast, deletion of EAF1 causes collapse of the NuA4 complex and displays 148 genetic interactions. Our study indicates that Eaf1 plays a crucial function in NuA4 complex integrity. Further, we determine that Eaf5 and Eaf7 form a subcomplex, which reflects their similar genetic interaction profiles and phenotypes. Our integrative study demonstrates that genetic interaction maps are valuable in dissecting complex structure and provides insight into why the human NuA4 complex, Tip60, has been associated with a diverse range of pathologies.

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