ATAC-king the complexity of SAGA during evolution.

Molecular Cancer Research, Netherlands Proteomics Center, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands.
Genes & development (Impact Factor: 12.64). 03/2012; 26(6):527-41. DOI: 10.1101/gad.184705.111
Source: PubMed

ABSTRACT The yeast SAGA (Spt-Ada-Gcn5-acetyltransferase) coactivator complex exerts functions in gene expression, including activator interaction, histone acetylation, histone deubiquitination, mRNA export, chromatin recognition, and regulation of the basal transcription machinery. These diverse functions involve distinct modules within this multiprotein complex. It has now become clear that yeast SAGA has diverged during metazoan evolution into two related complexes, SAGA and ATAC, which exist in two flavors in vertebrates. The compositions of metazoan ATAC and SAGA complexes have been characterized, and functional analyses indicate that these complexes have important but distinct roles in transcription, histone modification, signaling pathways, and cell cycle regulation.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Precise regulation of gene expression programs during embryo development requires cooperation between transcriptional factors and histone-modifying enzymes, such as the Gcn5 histone acetyltransferase. Gcn5 functions within a multi-subunit complex, called SAGA, that is recruited to specific genes through interactions with sequence-specific DNA-binding proteins to aid in gene activation. Although the transcriptional programs regulated by SAGA in embryos are not well defined, deletion of either Gcn5 or USP22, the catalytic subunit of a deubiquitinase module in SAGA, leads to early embryonic lethality. Here, we review the known functions of Gcn5, USP22 and associated proteins during development and discuss how these functions might be related to human disease states, including cancer and neurodegenerative diseases.
    Epigenomics 06/2014; 6(3):329-339. DOI:10.2217/epi.14.22 · 5.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Understanding the way how proteins interact with each other to form transient or stable protein complexes is a key aspect in structural biology. In this study, we combined chemical cross-linking with mass spectrometry to determine the binding stoichiometry and map the protein-protein interaction network of a human SAGA HAT subcomplex. MALDI-MS equipped with high mass detection was used to follow the cross-linking reaction using bis[sulfosuccinimidyl] suberate (BS3) and confirm the heterotetrameric stoichiometry of the specific stabilized subcomplex. Cross-linking with isotopically labeled BS3 d0-d4 followed by trypsin digestion allowed the identification of intra- and intercross-linked peptides using two dedicated search engines, pLink and xQuest. The identified inter-linked peptides suggest a strong network of interaction between GCN5, ADA2B and ADA3 subunits; SGF29 is interacting with GCN5 and ADA3 but not with ADA2B. These restraint data were combined to molecular modeling and a low resolution interacting model for the human SAGA HAT subcomplex could be proposed, illustrating the potential of an integrative strategy using cross-linking and mass spectrometry for addressing the structural architecture of multiprotein complexes. This article is protected by copyright. All rights reserved. © 2015 The Protein Society.
    Protein Science 03/2015; DOI:10.1002/pro.2676 · 2.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: While histone acetylation and deacetylation machineries (HATs and HDACs) regulate important aspects of cell function by targeting histone tails, recent work highlights that non-histone protein acetylation is also pervasive in eukaryotes. Here, we use quantitative mass-spectrometry to define acetylations targeted by the sirtuin family, previously implicated in the regulation of non-histone protein acetylation. To identify HATs that promote acetylation of these sites, we also performed this analysis in gcn5 (SAGA) and esa1 (NuA4) mutants. We observed strong sequence specificity for the sirtuins and for each of these HATs. While the Gcn5 and Esa1 consensus sequences are entirely distinct, the sirtuin consensus overlaps almost entirely with that of Gcn5, suggesting a strong coordination between these two regulatory enzymes. Furthermore, by examining global acetylation in an ada2 mutant, which dissociates Gcn5 from the SAGA complex, we found that a subset of Gcn5 targets did not depend on an intact SAGA complex for targeting. Our work provides a framework for understanding how HAT and HDAC enzymes collaborate to regulate critical cellular processes related to growth and division.
    Molecular &amp Cellular Proteomics 11/2014; 14(1). DOI:10.1074/mcp.M114.043141 · 7.25 Impact Factor

Full-text (2 Sources)

Available from
Nov 15, 2014