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Molecular and Cellular Biology, March 2004, p. 1884-1896, Vol. 24, No. 5
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.5.1884-1896.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Structural and Functional Conservation of the NuA4 Histone Acetyltransferase Complex from Yeast to Humans

Yannick Doyon,1 William Selleck,2 William S. Lane,3 Song Tan,2 and Jacques Côté1*

Laval University Cancer Research Center, Hôtel-Dieu de Québec, Quebec City, Quebec G1R 2J6, Canada,1 Center for Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802,2 Harvard Microchemistry Facility, Harvard University, Cambridge, Massachusetts 021383

Received 23 September 2003/ Returned for modification 22 October 2003/ Accepted 21 November 2003

The NuA4 histone acetyltransferase (HAT) multisubunit complex is responsible for acetylation of histone H4 and H2A N-terminal tails in yeast. Its catalytic component, Esa1, is essential for cell cycle progression, gene-specific regulation and has been implicated in DNA repair. Almost all NuA4 subunits have clear homologues in higher eukaryotes, suggesting that the complex is conserved throughout evolution to metazoans. We demonstrate here that NuA4 complexes are indeed present in human cells. Tip60 and its splice variant Tip60b/PLIP were purified as stable HAT complexes associated with identical polypeptides, with 11 of the 12 proteins being homologs of yeast NuA4 subunits. This indicates a highly conserved subunit composition and the identified human proteins underline the role of NuA4 in the control of mammalian cell proliferation. ING3, a member of the ING family of growth regulators, links NuA4 to p53 function which we confirmed in vivo. Proteins specific to the human NuA4 complexes include ruvB-like helicases and a bromodomain-containing subunit linked to ligand-dependent transcription activation by the thyroid hormone receptor. We also demonstrate that subunits MRG15 and DMAP1 are present in distinct protein complexes harboring histone deacetylase and SWI2-related ATPase activities, respectively. Finally, analogous to yeast, a recombinant trimeric complex formed by Tip60, EPC1, and ING3 is sufficient to reconstitute robust nucleosomal HAT activity in vitro. In conclusion, the NuA4 HAT complex is highly conserved in eukaryotes, in which it plays primary roles in transcription, cellular response to DNA damage, and cell cycle control.

* Corresponding author. Mailing address: Laval University Cancer Research Center, Hôtel-Dieu de Québec (CHUQ), 9 McMahon St., Quebec City, QC G1R 2J6, Canada. Phone: (418) 525-4444, ext. 15545. Fax: (418) 691-5439. E-mail: jacques.cote{at}crhdq.ulaval.ca.

Molecular and Cellular Biology, March 2004, p. 1884-1896, Vol. 24, No. 5
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.5.1884-1896.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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