The assembly of eukaryotic DNA into chromatin structure is essential for the faithful propagation of both the genetic and epigenetic information contained in our chromosomes. In addition, chromatin structure plays an intimate role in the proper progression of key cellular events such as transcription, DNA damage repair and recombination. Bringing together genomic DNA and histone proteins in an orderly manner is a complex process. As defects in chromatin structure are increasingly recognized as a key factor in diseases such as cancer, deciphering the molecular mechanisms at work in the assembly of chromatin is a critical step in developing an understanding of the role chromatin structure plays in the regulation of cell growth and development. 1 of the earliest events in the chromatin assembly process is the acetylation of lysine residues in the NH2-terminal tail domains of histones H3 and H4 that occurs rapidly following their synthesis. This is a universally conserved aspect of chromatin assembly in eukaryotes. This acetylation is catalyzed by type B histone acetyltransferases (HATs). To date, Hatlp is the only type B HAT that has been identified. We are using this enzyme as a starting point for determining how the acetylation of newly synthesized histones impacts the process of chromatin assembly. A number of recent developments have dramatically altered our picture of type B HATs and are the foundation for the current proposal. Amongst these is the observation that Hat1 p is not exclusively cytoplasmic and can also be found in the nucleus. While in the nucleus, Hatlp is associated with a novel yeast histone chaperone/chromatin assembly factor, Hiflp. In addition, the nuclear Hatlp complex is associated with histone H3 and H4 molecules that contain novel sites of post-translational modification in their globular core domain. We propose to extend these results through the following 3 specific aims. 1. Investigate the role of the type B histone acetyltransferase Hat1 p in the process of chromatin assembly. 2. Characterize the function of the histone chaperone Hiflp in histone deposition. 3. Characterize core domain modifications on histones H3 and H4 associated with chromatin assembly. ? ? ?
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