Functions of the MYST Family Histone Acetyltransferase Esal of Saccharomyces cerevisiae

Esa1 is the only histone acetyltransferase in Saccharomyces cerevisiae that is essential for viability. This enzymatic activity, directed primarily towards histone H4, has long been thought to be the essential function of Esa1 and its constituent NuA4 and Piccolo NuA4 complexes. However, no study to date has formally shown that catalysis is indispensable. Here we present evidence that the essential function of Esa1 does not involve its histone acetylation function. We show that a catalytically dead esa1 allele supports viability, and that loss of histone H4 acetylation by Esa1 correlates with sensitivity to a variety of stress agents. Strikingly, while catalysis is not required for viability, a structurally intact catalytic pocket does appear vital, suggesting that the essential function of Esa1 may involve cofactor and/or substrate recognition. To further understand the nature of the essential function of Esa1, we have also carried out a secondsite suppressor screen with a thermolabile esa1 allele. Two hits from the screen are components of the Rpd3L histone deacetylase complex, which has many functions that oppose those of NuA4 and Esa1. Surprisingly, the balance of histone acetylation and deacetylation may not play a prominent role in suppression. We propose a model in which Esa1 is an essential regulatory subunit of NuA4 activities, which include but are not limited to histone acetylation, and that loss of Esa1 results in catastrophic misregulation of one or more essential processes, leading to cell death.

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