Studying the multiple facets of the general SAGA transcription cofactor by cryogenic electron microscopy

SAGA’s many functions are essential for normal embryo development in flies and mice. Mutation or altered expression of SAGA subunits are associated with neurological disease and aggressive cancers in humans. Many early studies emphasised the mutually exclusive roles of SAGA and the related general transcription factor TFIID that shares a subset of subunits with SAGA. It was proposed that SAGA mostly regulates stress-inducible-genes, whereas TFIID is predominantly regulates housekeeping genes. The presumed specialised role of SAGA caused the transcription community to shift interest to other regulators, such as Mediator. However, recent studies have unequivocally established that SAGA functions as a general cofactor, universally required for Pol II transcription. It is therefore now crucial to reexamine former results in light of the role of SAGA as a general cofactor rather than a specialised coactivator. The lack of high-resolution structural information of the whole SAGA complex limits our understanding about how the different functions of SAGA contribute to regulation of gene expression. Specifically, interaction of SAGA with the preinitiation complex, whose formation is one of the most important regulatory events in Eukaryotic gene transcription, is poorly characterised and its significance not understood. Another enigmatic question is why the SAGA histone acetylation activity is restricted to promoter regions, whereas deubiquitination by the SAGA DUB module occurs across all gene bodies. We currently lack molecular-level understanding of the different interactions involved between components of the general machinery, SAGA and nucleosomes at the initiation and elongation transcriptional stages. We aim at filling this knowledge gap and take the first step toward understanding how SAGA contributes to regulation and deregulation of transcription in healthy and diseased states.