The SAGA continues: expanding the cellular role of a transcriptional co-activator complex

Abstract

Throughout the last decade, great advances have been made in our understanding of how DNA-templated cellular processes occur in the native chromatin environment. Proteins that regulate transcription, replication, DNA repair, mitosis and other processes must be targeted to specific regions of the genome and granted access to DNA, which is normally tightly packaged in the higher-order chromatin structure of eukaryotic nuclei. Massive multiprotein complexes have been discovered, which facilitate access to DNA and recruitment of downstream effectors through three distinct mechanisms: chemical modification of histone amino-acid residues, ATP-dependent chromatin remodeling and histone exchange. The yeast Spt-Ada-Gcn5-Acetyl transferase (SAGA) transcriptional co-activator complex regulates numerous cellular processes through coordination of multiple histone post-translational modifications. SAGA is known to generate and interact with a number of histone modifications, including acetylation, methylation, ubiquitylation and phosphorylation. Although best characterized for its role in regulating transcriptional activation, SAGA is also required for optimal transcription elongation, mRNA export and perhaps nucleotide excision repair. Here, we discuss findings from recent years that have elucidated the function of this 1.8-MDa complex in multiple cellular processes, and how misregulation of the homologous complexes in humans may ultimately play a role in development of disease.

Figure 1. Proposed model of SAGA activities that ensure smooth transition between transcription initiation, elongation, and mRNA export

(a) Upon transcriptional induction, SAGA is recruited to the gene promoter primarily through interaction with an acidic activator (Gal4 is shown) and loaded onto chromatin by the proteasome 19S RP. 19S RP interaction with monoubiquitin on H2B may be important for transcriptional regulation, as it is required for H3 Lys 4 trimethylation and may aid in targeting the 19S RP to the promoter region. SAGA interacts with trimethylation, phosphorylation and acetylation on histone H3. These interactions mediate further H3 acetylation by SAGA, which facilitates initiation of transcription. Removal of H2B monoubiquitin by SAGA is also important for transcriptional activation, and could allow progression of the 19S RP into the coding region. (b) Both SAGA and the 19S RP are associated with the coding regions of genes during transcriptional elongation, and SAGA may functionally interact with phosphorylation on the Pol II CTD. Histone H3 acetylation by SAGA in the coding region is important for nucleosome eviction. H2B ubiquitylation is also important for transcriptional elongation, and perhaps its removal within the coding region allows continued progression. (c) Eviction of acetylated nucleosomes allows increased processivity of Pol II. As nascent mRNA is formed, interactions between SAGA and components of the nuclear pore complex (NPC) maintain localization of actively transcribed genes to the nuclear periphery and allow for efficient coupling between synthesis and export. Dotted lines indicate physical interactions, black and red arrows designate addition and removal of post-translational modifications, respectively. 19S RP, 19S regulatory particle; Pol II CTD, polymerase II C-terminal domain; SAGA, Spt-Ada-Gcn5-Acetyl transferase.