Mechanistic Analysis of Chromatin Remodeling

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DESCRIPTION (provided by applicant) The packaging of DMA into chromatin makes it largely inaccessible for the central nuclear processes of transcription, replication, recombination and repair. ATP-dependent chromatin remodeling complexes play a key role in making chromatin dynamic. However, the mechanisms by which these complexes function are largely unknown. The overall goal of this proposal is to use the tools of mechanistic enzymology to understand how a major ATP-dependent chromatin remodeling complex, human SWI/SNF, catalyzes exposure of DMA from chromatin. SWI/SNF complexes play crucial roles in the transcriptional regulation of several genes as well in the cell cycle based regulation of chromosome structure. Consistent with these roles, mutations in the components of these complexes are associated with severe developmental defects and a variety of cancers. A detailed understanding of SWI/SNF mechanism will provide insights into how its activity is regulated and how it malfunctions. The specific aims of this project are: (1) To identify the individual steps in chromatin remodeling that lead to stable exposure of DNA. (2) To determine how SWI/SNF uses the energy of ATP binding and hydrolysis for remodeling chromatin. (3) To dissect the mechanistic contributions of individual SWI/SNF subunits.