STRUCTURE AND FUNCTION OF GENE REGULATORY COMPLEXES

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Gene regulation in cells requires the concerted action of gene specific activator and repressor proteins, general transcription factors, and chromatin modifying enzymes. These enzymes include the histone acetyltransferase multiprotein enzyme complexes which post-translationally acetylate the tails of histone protein components of chromatin. Since gene activity is well correlated with local histone acetylation in the cell, histone acetyltransferase complexes are likely to act as important coregulators of gene activity. The recent findings that such complexes also contain adaptor or coactivator proteins strengthened this relationship between histone acetylation and gene activation, and suggested that chromatin modifications and coactivator functions, such as recruitment to promoter regions, are coordinated processes. These activities may be involved in the development of human cancers since some of these coactivator proteins associate with cellular oncoproteins and tumor suppressor gene products. The long-term objectives of this proposal are to combine high-resolution structural descriptions with genetic and biochemical information to understand how eukaryotic gene regulatory complexes function. This proposal focuses on subcomplexes responsible for crucial functions of the yeast SAGA histone acetyltransferase complex. The primary goals include 1. analyzing the structure and function of the Ada2/Ada3/Gcn5 complex by biochemical methods, 2. determining the three-dimensional structure of the Ada2/Ada3/Gcn5 ternary complex by X-ray crystallography, 3. characterizing and crystallizing SAGA components bound to transcriptional activators and 4. characterizing and crystallizing SAGA components bound to general transcription factors.