SAGA complex as a multicomponent regulator of acetylation Essay

SAGA (Spt-Ada-Gcn5 acetyltransferase) is a large multisubunit protein in budding yeast Saccharomyces cerevisiae (Koutelou et al 2010). To date around 21 proteins have been identified to compose SAGA complex in yeast (Baker et al 2007). SAGA complex characterization has demonstrated the role of different groups of proteins Spt protein group has been found to interact with TATA binding protein (TBP), the Ada group has been shown to be responsible for nucleosomal HAT activity, the TATA binding proteins associated factor (TAF) proteins which mediate nucleosomal HAT activity by recruiting transcriptional machinery (Sterner et al 1999). Tra1, the largest subunit in SAGA complex is a protein that targets DNA bound activators for recruitment to promoter (Helmlinger 2012). SAGA is a highly conserved protein complex that has been identified in many eukaryotes including humans.
Histones can be modified by SAGA in different ways. The most characterized protein subunits of SAGA complex form the histone acetyltransferases (HAT) catalytic domain. This catalytic domain is responsible for the acetylation of H3 histone tails. The enzymatic activity of HATs has been identified as a major player in chromatin remodeling mechanisms (Sterner et al 1999).
However another important modification of chromatin structure is accomplished by the removal of an ubiquitin molecule from histone H2B (Figure 5). Lysine 123 of H2B ubiquitination and deubiquitination has been found to play an important role in the activation of gene expression (Rodrguez-Navarro 2009).
The process of ubiquitin removal is catalyzed by the Ubp8 subunit of SAGA co-activator complex together with three other proteins that compose the deubiquitination (DUB) module (Figure 7). The DUB module is composed of Ubp8 as its main catalytic domain and Sgf11, Sus1 and Sgf73, which functions as an anchor of the protein scaffold to SAGA complex. The DUB module has been characterized using crystal structures showing its binding to H2B and elucidating that the complex is bound to SAGA complex by the N terminal residues of Sgf73 subunit. Histone H2B ubiquitination is an important marker of actively transcribed genes. Therefore this module plays a role in regulation of gene transcription.
SAGA can be accounted for the transcription of 10% of yeast genes (Han, Yan, et al. 2012). These genes are mostly necessary for the proper response to external stresses. Different SAGA regulated genes have been identified one of great importance is GAL1. GAL genes have been used in gene expression studies because they provide a closely regulated system in which induction of gene expression can directly demonstrate changes in gene specific chromatin structure (Bash R 2001).
Previous studies on GAL genes have found that GAL1 activation is dependent on H2B ubiquitination (Baker et al 2007). The proposed mechanism indicates the collaboration between Rad6 and Ubp8 from SAGA complex. Rad6 binds to the promoter and due to its enzymatic activity, transcient binding of Rad6 to promoter regions is correlated to high levels of H2B ubiquitination. Binding of SAGA after dissociation of Rad6, allows for Ubp8 to remove ubiquitin. Proper activation of GAL1 gene requires presence of both proteins (Traven et al 2006).