Stress-inducible transcriptional control: the SAGA master regulator

Eukaryotic transcriptional co-activators are multi-subunit complexes that both modify chromatin and recognize histone modifications to control gene transcription. SAGA, short for Spt- Ada-Gcn5-Acetyl transferase, is one of the major transcriptional co-activator complexes in eukaryotes. SAGA is conserved from yeast to man and performs multiple functions during transcriptional activation and elongation by RNA polymerase II. A conserved set of TATA-box binding protein (TBP)-associated factors are shared between SAGA and the general transcription factor TFIID. Whilst TFIID regulates housekeeping genes, such as ribosomal protein genes, SAGA is of specific disease relevance as it controls the expression of stress-induced genes activated by key oncogenic transcription factors such as c-Myc. SAGA displays a more complex multi-modular architecture than TFIID, with each module harbouring a distinct functional role or enzymatic activity directly linked to human disease. Mutation or altered expression of SAGA subunits is associated with neurological disease and aggressive cancers in humans. SAGA is recruited to specific target genes by key oncogenic transcription factors to activate and regulate gene transcription. SAGA’s many functions are essential for normal embryo development in flies and mice. However, the paucity of detailed knowledge about the mechanisms that turn on/off the different enzymatic activities of SAGA throughout the transcription cycle has precluded the development of targeted therapies. Several studies have shown that the activities of the enzymatic subunits of SAGA are altered when they are incorporated into larger subcomplexes, underscoring the need for structural information of the complete SAGA assembly to enable structure-guided approaches to inform the design of new therapies.