Structural Biology of Sin3 Corepressor

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DESCRIPTION (provided by applicant): Regulation of eukaryotic gene expression at the transcriptional level relies on the coordinated action of multiple protein factors. Recruitment of multi-protein cofactor complexes containing chromatin-modifying and/or chromatin-remodeling activities by sequence-specific DNA binding factors appears to be a common, highly conserved mechanism of regulating gene transcription at many promoters. The Sin3 corepressor complex is one of two major repression machineries identified thus far in mammalian cells. The negative influence on gene transcription exerted by these corepressor complexes is thought to rely in part on the action of histone deacetylases (HDACs), a group of enzymes that catalyze the hydrolysis of acetyl groups from acetylated histone substrates. The Sin3 corepressor functions as a molecular adapter specifically associating with HDAC1 and HDAC2 on the one hand and a surprisingly large and diverse group of transcription factors that play crucial roles in normal development on the other. The structural basis for such macromolecular associations, which has important implications in the strict regulation of gene transcription, is poorly understood. Our studies will address fundamental questions including, how Sin3 interacts with its targets at the atomic level, why it interacts specifically with these targets but not with others, and which residues make important contributions towards the stability of these macromolecular associations. Answers to these questions rely largely on detailed structure-function analyses. Our primary tool for these investigations will be high-resolution liquid-state NMR spectroscopy but we will also pursue biochemical and other biophysical approaches, as necessary.