The highly conserved and multifunctional NuA4 HAT complex

Abstract

Histone acetyltransferase complexes have been shown to be key regulators of gene expression. Among these, the NuA4 complex, first characterized in yeast, stands out as it controls multiple key nuclear functions in eukaryotic cells. Many subunits of this protein assembly have been directly linked to global and targeted acetylation of histone H4 tails in vivo, regulation of transcription, cell-cycle progression as well as to the process of DNA repair. Recent studies presented here have established its remarkable structural conservation from yeast to human cells and contributed to the understanding of its diverse functions.

Introduction

The role of chromatin as a dynamic and active participant in multiple nuclear processes was first recognized by its ability to regulate gene expression in eukaryotic cells. One way of modulating that structure is by the post-translational modification of the histones present in the minimal chromatin unit: the nucleosome. Several modifications have been described, including acetylation, methylation, phosphorylation, ubiquitination and ADP-ribosylation. The long-standing link between histone acetylation and transcriptional activity coupled to the breakthrough discovery that the evolutionary conserved Gcn5 co-activator was a histone acetyltransferase (HAT) led to the search, identification and characterization of many such enzymes. Histone acetylation has been proposed to play a dual role in the cell. First, the covalent addition of acetyl groups to specific lysine residues neutralizes the positive charge of the histone tail, which weakens histone–DNA contacts within the nucleosome and/or histone–histone contacts involved in higher-order chromatin structure. Acetylation of histones also provides an epigenetic marker for gene expression because it blocks association of heterochromatin-stabilizing complexes like SIR and it can be recognized by protein domains, such as bromodomains, present in various components of the transcription machinery. Thus, post-translational modifications of histones do not just change chromatin structure directly, they also modulate interaction of specific proteins with chromatin 1., 2., 3., 4..

HATs have been grouped in five distinct families on the basis of sequence homology. The best-characterized group is the GNAT (Gcn5-related N-acetyltransferase) family that includes yeast Gcn5 and human Gcn5/PCAF 5., 6., 7.. Another large group of evolutionary related HAT enzymes is the MYST family (named for its founding members: MOZ, Ybf2/Sas3, Sas2 and Tip60). Apart from their role as specific transcription co-activators, MYST proteins are involved in a wide variety of cell functions such as gene silencing in yeast, dosage compensation in Drosophila and oncogenic transformation leading to specific human diseases such as leukemia 7., 8.. Most of these HATs are part of large multisubunit protein complexes. Those protein machines are modular and their subunit composition confers on them their ability to bind their substrate and control various nuclear functions. The purpose of this article is to review the biochemical composition and cellular functions of a specific MYST HAT, the NuA4 (nucleosome acetyltransferase of H4) complex, a key regulator of transcription, cellular response to DNA damage and cell cycle control.