Insights into SAGA function during gene expression

Abstract

Histone modifications are a crucial source of epigenetic control. SAGA (Spt-Ada-Gcn5 acetyltransferase) is a chromatin-modifying complex that contains two distinct enzymatic activities, Gcn5 and Ubp8, through which it acetylates and deubiquitinates histone residues, respectively, thereby enforcing a pattern of modifications that is decisive in regulating gene expression. Here, I discuss the latest contributions to understanding the roles of the SAGA complex, highlighting the characterization of the SAGA-deubiquitination module, and emphasizing the functions newly ascribed to SAGA during transcription elongation and messenger-RNA export. These findings suggest that a crosstalk exists between chromatin remodelling, transcription and messenger-RNA export, which could constitute a checkpoint for accurate gene expression. I focus particularly on the new components of human SAGA, which was recently discovered and confirms the conservation of the SAGA complex throughout evolution.

Figure 1

The SAGA deubiquitination module is conserved from yeast to humans. (A) The yeast DUBm is composed of Ubp8, Sgf11 and Sus1. The elimination of ubp8, sgf11 or sus1 induces a pair-wise loss of the other members of the module and impairs SAGA association. (B) The human DUBm contains USP22, ATXN7L3 and ENY2. A direct interaction between ATXN7L3–USP22 and ATXN7L3–ENY2 has been shown in human cells. ATXN7L3, ataxin 7-like 3; DUBm, deubiquitination module; ENY2, human homologue of enhancer of yellow 2; SAGA, Spt–Ada–Gcn5 acetyltransferase; Sgf11, SAGA-associated factor 11; Sus1, Sl gene upstream of ySa1; Ubp8, ubiquitin-specific processing protease 8; USP22, ubiquitin-specific peptidase 22.

Figure 2

ATXN7/Sgf73 anchors the SAGA deubiquitination module to SAGA. A loss of Sgf73 prevents DUBm–SAGA association. Ubp8, Sgf11 and Sgf73 were found to interact in DUBm purified from cells lacking spt20, which is required for SAGA stability and recruitment to promoters. In these cells, Sus1 is not associated with the submodule, indicating that SAGA has a role in DUBm assembly. ATXN7, ataxin 7; DUBm, deubiquitination module; ENY2, human homologue of enhancer of yellow 2; SAGA, Spt–Ada–Gcn5 acetyltransferase; Sgf, SAGA-associated factor; spt, suppressor of Ty element; Sus1, Sl gene upstream of ySa1; Taf5, TATA-binding protein-associated factor 5; Ubp8, ubiquitin-specific processing protease 8; USP22, ubiquitin-specific peptidase 22.

Figure 3

Different SAGA subunits are involved in transcription elongation. The coordination of SAGA enzymatic activities helps transcription through coding regions. Among other SAGA components, Gcn5 and Ubp8 are recruited to coding regions to modify histones, which, in turn, facilitate transcription elongation. Gcn5 promotes nucleosome eviction and Ubp8 activity contributes to Ctk1 recruitment. Sus1 enters the coding regions and interacts physically with phosphorylated RNAPII and the mRNA-export factors Yra1 and Mex67 cotranscriptionally, ensuring an optimal coupling between transcription elongation and mRNA export. Cdc31, cell division cycle 31; Ctk1, carboxy-terminal domain kinase 1; DUBm, deubiquitination module; Gcn5, general control nonderepressible 5; Mex67, messenger RNA export protein 67; NPC, nuclear pore complex; RNAPII, RNA polymerase II; Sac3, suppressor of actin 3; SAGA, Spt–Ada–Gcn5 acetyltransferase; Sus1, Sl gene upstream of ySa1; Thp1, Tho2/Hpr1 phenotype; TREX2, transcription export 2; Ub, ubiquitin; Ubp8, ubiquitin-specific processing protease 8; Yra1, yeast RNA annealing protein 1.

Figure 4

SAGA is involved in messenger RNA export and gene gating. (A) Deletion studies have shown that the middle domain of Sgf73 is required for SAGA binding and to preserve the integrity of TREX2. Through its bifunctional protein design, Sgf73 could contribute to creating a link to the export of specific mRNA transcripts across the NPC. (B) Deletion of sgf73 causes the partial disassembly of the TREX2 complex, and the mislocalization of Sus1, Sac3 and Thp1 away from the NPC and in the cytoplasm. In this mutant, gal1 transcripts are unable to leave the nucleus. Cdc31, cell division cycle 31; DUBm, deubiquitination module; GAL1, galactose metabolism 1; NPC, nuclear-pore complex; Sac3, suppressor of actin 3; SAGA, Spt–Ada–Gcn5 acetyltransferase; Sgf, SAGA-associated factor; Sus1, Sl gene upstream of ySa1; Thp1, Tho2/Hpr1 phenotype; TREX2, transcription export 2; Ub, ubiquitin.

Susana Rodríguez-Navarro