Functional Analysis of SWI/SNF chromatin remodelers

Research Inst Of Fox Chase Can Ctr, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to understand how ATP-dependent chromatin-remodeling complexes regulate nuclear events, maintain normal cell growth and prevent cancer formation. Cellular transformation is often caused by aberrant expression of genes involved in growth control. Chromatin remodeling complexes function as transcription co-regulators and have been found to play a role in cell-cycle progression. BRG1 and INI1/hSNF5, two conserved subunits of SWI/SNF, appear to behave as classical tumor suppressors. Mutations in BRG1 have been found in multiple human tumor cell lines, and the INI1/hSNF5 subunit is often mutated in rhabdoid sarcomas, a very aggressive pediatric cancer. Mutations or deletions of other conserved components of human SWI/SNF complexes have also been detected in a number of chronic and acute leukemias, CNS tumors and human adenocarcinomas. Increasing numbers of ATP-dependent chromatin-remodeling complexes are being identified. Each of them has an ATPase core subunit, and some of these ATPase subunits have been demonstrated to function as motor proteins. The SWI/SNF and ISWl families are the best understood among ATP-dependent chromatin remodeling complexes. BRG1 and SNF2h are the motors for the most prominent human SWI/SNF and ISWl families, respectively. A fundamental question is how the ATP-hydrolysis activities of similar core subunits, such as BRG1 and SNF2h, can be used to accomplish distinct chromatin remodeling reactions, and how these proteins differentially contribute to regulate chromatin structure. This application proposes a detailed comparison of ATP-dependent chromatin remodeling mechanisms, and an investigation into how mechanistic differences might impact upon gene expression in vivo. Results from these experiments will increase our understanding of how different classes of remodeling mechanisms control different biological processes.