The broad, long-term goal of the proposed study is to determine, at the molecular level, the mechanisms by which chromatin structure is regulated. We believe this study is important, since chromatin structure plays critical roles in many essential biological processes that rely on protein-DNA interactions, such as transcription, DNA replication, DNA repair and recombination. Consistent with the important roles of chromatin in cells, mutations and mis-regulation of chromatin remodeling factors, proteins that regulate chromatin structure, are frequently found in malignant human diseases, such as leukemia and solid tumors. Therefore, uncovering the mechanisms of chromatin regulation will not only advance our knowledge of essential biological processes, but also the underlying mechanisms of human diseases. To this end, we propose a series of experiments to identify the functions and the mechanisms of action of Isw1 and Isw2 chromatin remodeling complexes using the budding yeast, Saccharomyces cerevisiae, as a model organism. Both Isw1 and Isw2 belong to a group of chromatin remodeling complexes that are highly conserved from yeast to humans. Therefore, what we learn in this system will have general implications. We will take advantage of powerful molecular genetic and biochemical tools available in this organism to accomplish our goal. Specifically, we will: (1) Determine the mechanisms of Isw2 complex-dependent chromatin remodeling by using a conditional allele of the ISW2 gene. (2) Determine how Isw2 complex is targeted and regulated in cells. (3) Identify additional functions of Isw2 complex. (4) Identify functions of Isw1 complex in cells.
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