Distinct GCN5/PCAF-containing complexes function as co-activators and are involved in transcription factor and global histone acetylation

Abstract

Transcription in eukaryotes is a tightly regulated, multistep process. Gene-specific transcriptional activators, several different co-activators and general transcription factors are necessary to access specific loci to allow precise initiation of RNA polymerase II transcription. As the dense chromatin folding of the genome does not allow the access of these sites by the huge multiprotein transcription machinery, remodelling is required to loosen up the chromatin structure for successful transcription initiation. In the present review, we summarize the recent evolution of our understanding of the function of two histone acetyl transferases (ATs) from metazoan organisms: GCN5 and PCAF. Their overall structure and the multiprotein complexes in which they are carrying out their activities are discussed. Metazoan GCN5 and PCAF are subunits of at least two types of multiprotein complexes, one having a molecular weight of 2 MDa (SPT3-TAF9-GCN5 acetyl transferase/TATA binding protein (TBP)-free-TAF complex/PCAF complexes) and a second type with about a size of 700 kDa (ATAC complex). These complexes possess global histone acetylation activity and locus-specific co-activator functions together with AT activity on non-histone substrates. Thus, their biological functions cover a wide range of tasks and render them indispensable for the normal function of cells. That deregulation of the global and/or specific AT activities of these complexes leads to the cancerous transformation of the cells highlights their importance in cellular processes. The possible effects of GCN5 and PCAF in tumorigenesis are also discussed.

MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells

“…Like HAT1, Gcn5, PCAF and many other HATs Lee and Workman, 2007;Nagy and Tora, 2007;Parthun, 2007), MOZ and MORF are catalytic components of protein complexes. They were recently found to be stoichiometric subunits of ING5 (inhibitor of growth 5) complexes (Doyon et al, 2006).…”

Subunits of ADA-two-A-containing (ATAC) or Spt-Ada-Gcn5-acetyltrasferase (SAGA) Coactivator Complexes Enhance the Acetyltransferase Activity of GCN5

“…H3 tail peptide covering amino acids 5-20 was incubated with radioactive acetyl-coenzyme A and the indicated protein or protein complex preparation. Reactions were carried out in quadruplicate in the presence (H3 amino acids [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] or absence of the H3 tail peptide, and acetylation was measured in cpm. Error bars indicate S.D.…”

“…Later it was shown that this enzyme is homologous to the yeast Gcn5 protein, already known to be required for transcriptional activation (7)(8)(9)(10). Gcn5 is evolutionary highly conserved from yeast to human (5,11). Initial in vitro studies using microsequencing of labeled yeast histone H3 or H4 peptides and recombinant Gcn5 indicated that the enzyme displays a non-random specificity, mainly acetylating histone H3 at Lys-14 and to some extent H4 at Lys-8 position (12).…”

“…This modification is thought to activate gene expression by loosening the chromatin structure but also by creating docking surfaces for other proteins and protein complexes (2)(3)(4)(5). GCN5 (also called KAT2A) was the first histone acetyltransferase (HAT) 5 or lysine (K) acetyltransferase (KAT) -enzyme to be identified and was classified to be part of the GNAT (Gcn5-related N-acetyltransferase) family of enzymes. Its activity as an acetyltransferase on histone substrates was first described in Tetrahymena (6).…”

TAF4b and Jun/Activating Protein-1 Collaborate to Regulate the Expression of Integrin α6 and Cancer Cell Migration Properties

“…The involvement of other TAFs in cancer and/or metastasis has already been brought into light (7,46), however, this is the first report linking TAF4b itself with the regulation of tumor cell migration. Herewith, we provide evidence that TAF4b is a suppressor of cell migration regulating, in concert with c-Jun, the expression of genes playing a pivotal role in EMT.…”