There is a fundamental paradox within the nucleus of every eukaryotic cell: The genetic material must be organized and compacted yet remain accessible for readout by transcription machinery. Two of the many factors that retain this balance are histones and histone binding proteins. Histones are ultimately responsible for compacting the chromosomal DNA almost 500,000-fold to fit into the nucleus. While genome accessibility is regulated in part by the actions of histone acetyltransferases (KATs), histone chaperones interact directly with histones and can assemble and/or disassemble them on DNA. KATs covalently modify the histones and therefore have the potential to alter chromatin structure. Exciting new evidence structurally and functionally link KATs and histone chaperones. However, virtually nothing is known about the mechanisms by which these proteins cooperate to manage compaction and genome accessibility. To begin to understand this important biological question, this project proposes to study the histone acetyltransferase (KAT) Rtt109 as a model system. Rtt109 employs two structurally unrelated histone chaperones, Vps75 and Asf1. In vivo, Vps75 has been shown to directly interact with Rtt109, but only Asf1 is required for Rtt109 function. Both chaperones activate Rtt109 acetyltransferase activity in vitro, but Rtt109 acetylates histones in multiple locations, and Vps75 and Asf1 appear to alter Rtt109 specificity. A biochemical and molecular understanding of how specificity and selectivity is achieved is currently a major challenge in the chromatin field. This project will employ and expand on new methodologies for studying complex protein-protein networks needed to regulate chromatin dynamics and post-translational specificity.
Regulation of gene expression and chromatin dynamics by epigenetic factors such as histone modification has shown promise in the treatment of many of the major human diseases. Limiting the success of anti- modification drugs has been a lack of knowledge on how modification enzymes differentiate substrates and how their ability to modify multiple positions on a single substrate is regulated. Knowledge of this mechanism will provide unprecedented insight into genome regulation, facilitating new therapies that target specific sites by altering selectivity, which would be a significant improvement over current enzyme inhibition approaches.
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