title: Chromatin Regulation by the NuA4 Acetyltransferase Complex Is Mediated by Essential Interactions Between Enhancer of Polycomb (Epl1) and Esa1.
abstract: Enzymes that modify and remodel chromatin act in broadly conserved macromolecular complexes. One key modification is the dynamic acetylation of histones and other chromatin proteins by opposing activities of acetyltransferase and deacetylase complexes. Among acetyltransferases, the NuA4 complex containing Tip60 or itsSaccharomyces cerevisiaeortholog Esa1 is of particular significance because of its roles in crucial genomic processes including DNA damage repair and transcription. The catalytic subunit Esa1 is essential, as are five noncatalytic NuA4 subunits. We found that of the noncatalytic subunits, deletion of Enhancer of polycomb (Epl1), but not the others, can be bypassed by loss of a major deacetylase complex, a property shared by Esa1 Noncatalytic complex subunits can be critical for complex assembly, stability, genomic targeting, substrate specificity, and regulation. Understanding the essential role of Epl1 has been previously limited, a limitation now overcome by the discovery of its bypass suppression. Here, we present a comprehensivein vivostudy of Epl1 using the powerful tool of suppression combined with transcriptional and mutational analyses. Our results highlight functional parallels between Epl1 and Esa1 and further illustrate that the structural role of Epl1 is important for promotion of Esa1 activity. This conclusion is strengthened by our dissection of Epl1 domains requiredin vivofor interaction with specific NuA4 subunits, histone acetylation, and chromatin targeting. These results provide new insights for the conserved, essential nature of Epl1 and its homologs, such as EPC1/2 in humans, which is frequently altered in cancers.
authors.affiliation: Biomedical Sciences, University of California, San Diego, La Jolla, California 92093.|Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, UC San Diego Moores Cancer Center, La Jolla, California 92093.
authors.forename: Naomi E
authors.identifier: 0000-0002-5208-9700
authors.initials: NE
authors.lastname: Searle
authors.affiliation: Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, UC San Diego Moores Cancer Center, La Jolla, California 92093.
authors.forename: Ana Lilia
authors.identifier: 0000-0003-3100-6897
authors.initials: AL
authors.lastname: Torres-Machorro
authors.affiliation: Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, UC San Diego Moores Cancer Center, La Jolla, California 92093 lpillus@ucsd.edu.
authors.forename: Lorraine
authors.identifier: 0000-0002-8818-5227
authors.initials: L
authors.lastname: Pillus
mesh_terms: D001665:Binding Sites; D042002:Chromatin Assembly and Disassembly; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029701:Saccharomyces cerevisiae Proteins; C580641:Epl1 protein, S cerevisiae; C496551:Esa1 protein, S cerevisiae; D051548:Histone Acetyltransferases; C504740:NuA4 protein, S cerevisiae
keywords: EPL1; ESA1; NuA4; acetylation; chromatin