title: Eaf1 is the platform for NuA4 molecular assembly that evolutionarily links chromatin acetylation to ATP-dependent exchange of histone H2A variants.
abstract: Eaf1 (for Esa1-associated factor 1) and Eaf2 have been identified as stable subunits of NuA4, a yeast histone H4/H2A acetyltransferase complex implicated in gene regulation and DNA repair. While both SWI3-ADA2-N-CoR-TF IIIB domain-containing proteins are required for normal cell cycle progression, their depletion does not affect the global Esa1-dependent acetylation of histones. In contrast to all other subunits, Eaf1 is found exclusively associated with the NuA4 complex in vivo. It serves as a platform that coordinates the assembly of functional groups of subunits into the native NuA4 complex. Eaf1 shows structural similarities with human p400/Domino, a subunit of the NuA4-related TIP60 complex. On the other hand, p400 also possesses an SWI2/SNF2 family ATPase domain that is absent from the yeast NuA4 complex. This domain is highly related to the yeast Swr1 protein, which is responsible for the incorporation of histone variant H2AZ in chromatin. Since all of the components of the TIP60 complex are homologous to SWR1 or NuA4 subunits, we proposed that the human complex corresponds to a physical merge of two yeast complexes. p400 function in TIP60 then would be accomplished in yeast by cooperation between SWR1 and NuA4. In agreement with such a model, NuA4 and SWR1 mutants show strong genetic interactions, NuA4 affects histone H2AZ incorporation/acetylation in vivo, and both preset the PHO5 promoter for activation. Interestingly, the expression of a chimeric Eaf1-Swr1 protein recreates a single human-like complex in yeast cells. Our results identified the key central subunit for the structure and functions of the NuA4 histone acetyltransferase complex and functionally linked this activity with the histone variant H2AZ from yeast to human cells.
authors.affiliation: Laval University Cancer Research Center, Hôtel-Dieu de Québec (CHUQ), 9 McMahon St., Quebec City, Quebec G1R 2J6, Canada.
authors.forename: Andréanne
authors.initials: A
authors.lastname: Auger
authors.forename: Luc
authors.initials: L
authors.lastname: Galarneau
authors.forename: Mohammed
authors.initials: M
authors.lastname: Altaf
authors.forename: Amine
authors.initials: A
authors.lastname: Nourani
authors.forename: Yannick
authors.initials: Y
authors.lastname: Doyon
authors.forename: Rhea T
authors.initials: RT
authors.lastname: Utley
authors.forename: Dominique
authors.initials: D
authors.lastname: Cronier
authors.forename: Stéphane
authors.initials: S
authors.lastname: Allard
authors.forename: Jacques
authors.initials: J
authors.lastname: Côté
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000737:chemistry / Q000502:physiology*; D000135:Acid Phosphatase; D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000502:physiology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism*; D005057:Eukaryotic Cells / Q000378:metabolism; D019143:Evolution, Molecular; D051548:Histone Acetyltransferases / Q000737:chemistry / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D011401:Promoter Regions, Genetic; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017434:Protein Structure, Tertiary; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013045:Species Specificity; D013329:Structure-Activity Relationship
chemical_list: D002843:Chromatin; D006657:Histones; C493530:Htz1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C503153:Swc4 protein, S cerevisiae; D000255:Adenosine Triphosphate; D000123:Acetyltransferases; C528254:Eaf1 protein, S cerevisiae; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; C504740:NuA4 protein, S cerevisiae; D000135:Acid Phosphatase; C488916:PHO5 protein, S cerevisiae; D000251:Adenosine Triphosphatases; C481261:Swr1 protein, S cerevisiae; C119652:SRCAP protein, human