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What Do the Structures of GCN5-Containing Complexes Teach Us About Their Function? Dominique Helmlinger, Gábor Papai, Didier Devys, Làszlo Tora

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What Do the Structures of GCN5-Containing Complexes Teach Us About Their Function? Dominique Helmlinger, Gábor Papai, Didier Devys, Làszlo Tora What do the structures of GCN5-containing complexes teach us about their function? Dominique Helmlinger, Gábor Papai, Didier Devys, Làszlo Tora To cite this version: Dominique Helmlinger, Gábor Papai, Didier Devys, Làszlo Tora. What do the structures of GCN5- containing complexes teach us about their function?. Biochimica et Biophysica Acta - Gene Regulatory Mechanisms , Elsevier, 2020, pp.194614. 10.1016/j.bbagrm.2020.194614. hal-02990243 HAL Id: hal-02990243 https://hal.archives-ouvertes.fr/hal-02990243 Submitted on 5 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution - NonCommercial - NoDerivatives| 4.0 International License BBA - Gene Regulatory Mechanisms xxx (xxxx) xxxx Contents lists available at ScienceDirect BBA - Gene Regulatory Mechanisms journal homepage: www.elsevier.com/locate/bbagrm Review What do the structures of GCN5-containing complexes teach us about their ☆ function? ⁎ ⁎ Dominique Helmlingera, Gábor Papaib,c,d,e, Didier Devysb,c,d,e, , László Torab,c,d,e, a CRBM, University of Montpellier, CNRS, Montpellier, France b Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France c Centre National de la Recherche Scientifique (CNRS), UMR7104, 67404 Illkirch, France d Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, 67404 Illkirch, France e Université de Strasbourg, 67404 Illkirch, France ARTICLE INFO ABSTRACT Keywords: Transcription initiation is a major regulatory step in eukaryotic gene expression. It involves the assembly of Transcription general transcription factors and RNA polymerase II into a functional pre-initiation complex at core promoters. Chromatin The degree of chromatin compaction controls the accessibility of the transcription machinery to template DNA. KAT2A Co-activators have critical roles in this process by actively regulating chromatin accessibility. Many transcrip- KAT2B tional coactivators are multisubunit complexes, organized into distinct structural and functional modules and ADA complex carrying multiple regulatory activities. The first nuclear histone acetyltransferase (HAT) characterized was SAGA complex ADA two A containing (ATAC) complex General Control Non-derepressible 5 (Gcn5). Gcn5 was subsequently identified as a subunit of the HAT module Modular organization of the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex, which is an experimental paradigm for multifunctional Histone acetyl transferase co-activators. We know today that Gcn5 is the catalytic subunit of multiple distinct co-activator complexes with Histone deubiquitylase specific functions. In this review, we summarize recent advances in the structure of Gcn5-containing co-activator complexes, most notably SAGA, and discuss how these new structural insights contribute to better understand their functions. This article is part of a Special Issue entitled: Gcn5: the quintessential histone acetyltransferase. 1. Introduction different properties (structural, chromatin readers or writers…), raising questions on the advantages of their partition in different complexes Transcription initiation is a major regulatory step in eukaryotic gene and on the mechanisms controlling the biogenesis of these specific as- expression. The accessibility of the transcription machinery to template semblies. DNA is controlled by the degree of chromatin compaction. Co-activators The first nuclear histone acetyltransferase (HAT) identified was have critical roles in this process, bridging DNA-bound transcription General Control Non-derepressible 5 (Gcn5) [1,2]. Gcn5 was rapidly factors to the general transcription machinery, while actively regulating shown to function as a subunit of the Spt-Ada-Gcn5-acetyltransferase chromatin accessibility. Many transcriptional coactivators are multi- (SAGA) complex, which is a paradigmatic example of such multi- subunit complexes carrying multiple regulatory activities, including functional co-activators. We now know that Gcn5 is the catalytic histone modification, ATP-dependent nucleosome remodeling or in- component of multiple co-activator complexes with distinct functions. corporation of histone variants. Combining different activities into a In this review, we summarize recent advances in our understanding of single entity may be important to coordinate their activities during the the structure/function relationship of these GCN5-containing co-acti- transcription cycle. Genetic, biochemical and structural studies con- vator complexes. sistently reported that the activities of coactivators are carried by dis- tinct structural and functional modules. A given module can be shared between different complexes, which can therefore be considered as specific assemblies of individual modules, selected during evolution for their role in chromatin regulation. The shared subunits have very ☆ This article is part of a Special Issue entitled: Gcn5: the quintessential HAT edited by Dr. Vikki Weake. ⁎ Corresponding authors at: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France. E-mail addresses: [email protected] (D. Devys), [email protected] (L. Tora). https://doi.org/10.1016/j.bbagrm.2020.194614 Received 15 May 2020; Received in revised form 28 July 2020; Accepted 29 July 2020 1874-9399/ © 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). Please cite this article as: Dominique Helmlinger, et al., BBA - Gene Regulatory Mechanisms, https://doi.org/10.1016/j.bbagrm.2020.194614 D. Helmlinger, et al. BBA - Gene Regulatory Mechanisms xxx (xxxx) xxxx Table 1 known to interact physically [10,11]. In contrast, Ada1 and Ada5 Summary of SAGA subunit composition across eukaryotic species. Shown are (Spt20) are only found in SAGA. Both Ada2 and Ada3 were shown to be the names of each subunit from Saccharomyces cerevisiae, Drosophila melanoga- required for the HAT activity of Gcn5 and mutations in the corre- ster, Homo sapiens, and Arabidopsis thaliana, according to official nomenclatures. sponding genes cause similar phenotypes [12]. The association of these Names in brackets are alternative, commonly used names. Paralogous subunits three proteins confers Gcn5 the ability to acetylate nucleosomal his- are separated with a “/” sign and are indicated if they have been described as tones, whereas Gcn5 alone acetylates only free histones [2,3,13]. Later part of SAGA. In most cases, paralogous subunits are mutually exclusive within work identified Sgf29, a fourth component of the HAT module [14,15]. SAGA complexes. Individual module subunits are colored according to the code used in Fig. 1. “-”: no ortholog detected. “X”: ortholog exists but is not present The discovery of these four proteins in these two complexes, in which in SAGA. #It is unclear whether HAF1 and HAF2 are bona fide SAGA compo- they form a shared HAT module, was the first step towards the un- nents and genuine orthologs of Spt7 in plants. HFD: histone fold domain. *The derstanding of the modular organization of the SAGA complex TBP binding module comprises both Spt3 and Spt8 in S. cerevisiae, but pre- (Table 1). sumably only Spt3 in plants and animals. øBased on HFD conservation it has Genetic and functional overlap between Ada and proteins isolated been suggested that most plants have rather a TAF13 ortholog, than a SPT3 as suppressors of Ty and solo δ insertion mutations in yeast (Spt) led to ortholog [132]. the identification of additional SAGA components. Indeed, all Spt pro- teins that are functionally linked to the TATA-binding protein (TBP/ Orthologous SAGA complexes Spt15), namely Spt3, Spt7, Spt8 and Spt20 (Ada5), were found to physically interact with Gcn5, Ada2 and Ada3 [3,16]. These SAGA tools S. cerevisiae D. melanogaster H. sapiens A. thaliana subunits were classified in two groups according to the phenotypes of their mutants and to their roles in complex assembly [4,17]. Mutations KAT2 KAT2A/KAT2B Gcn5 GCN5 in S. cerevisiae SPT20/ADA5, SPT7, and ADA1 cause severe growth (GCN5) (GCN5/PCAF) phenotypes and are crucial for SAGA structural integrity [4,17]. Spt3 HAT Ada2 Ada2b TADA2b ADA2b and Spt8 mutants exhibit milder growth phenotypes, are not crucial for SAGA integrity, and interact genetically with TBP in S. cerevisiae module Ngg1 (Ada3) Ada3 TADA3 ADA3 [17–19]. These landmark studies gave the first hints suggesting that SGF29a/ Sgf29 Sgf29 SGF29 distinct SAGA subunits may assemble in three discrete functional SGF29b modules: a HAT module (Ada2, Ada3 and Gcn5), a TBP-interaction Ubp8 dNonstop USP22 (UBP22) UBP22 module (Spt3 and Spt8) and a structural module (Ada1, Spt7 and Spt20) (Table 1). DUB Sgf11 dSgf11 ATXN7L3 SGF11 Further analyses of native SAGA complexes purified from S. cerevi- ATXN7/ module Sgf73 dATXN7 ATXN7L1/L2 siae identified a subset of TBP-associated factors (TAFs) shared with the TFIID complex (Taf5, Taf6, Taf9, Taf10 and Taf12) as integral compo- Sus1 dE(y)2 ENY2 ENY2 nents of SAGA [20]. Four of
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