ATP-dependent chromatin remodeling is a key regulatory component of nuclear events, such as DNA replication, repair, recombination and transcription. Misregulation of these events can lead to disordered gene expression, failed DNA damage response and subsequent genome instability, all of which are major causes of human cancer. The long-term objective of my research is to understand how chromatin remodeling regulates these events and how this regulation may be altered in cancer cells. We have identified a single-component chromatin remodeling factor previously designated as Fun30 in yeast. Deletion of yeast FUN30 renders cells sensitive to DNA damaging agents. Overexpression of FUN30 or its human homolog has been implicated in causing genome instability. Biochemical studies show that Fun30 exhibits an ATP-dependent nucleosome sliding activity. However, little is known about the chromatin remodeling function of Fun30 in vivo. We hypothesize that the ATP dependent chromatin remodeling by Fun30 regulates nucleosome positioning in vivo. Using the yeast Saccharomyces cerevisiae as model system and the state-of-the-art techniques, we propose to: 1) Determine the chromatin remodeling function of Fun30 by chromosome-wide mapping of changes in Fun30 dependent nucleosome positioning. 2) Determine the biological targets of Fun30 by genome-wide mapping of Fun30 localization using high density ChlP-chip. 3) Functional analysis of Fun30 at its target genes. The successful completion of these studies will provide the first genome-wide examination of nucleosome positioning regulated by ATP-dependent chromatin remodeling. It will also provide insight into the functional significance of Fun30 mediated chromatin remodeling for transcription and other nuclear events.
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