HISTONE NUCLEAR IMPORT AND CHROMATIN ASSEMBLY

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DESCRIPTION (provided by applicant):The long term goal of this project is to understand how the nuclear import of histones and chromatin-associated factors is regulated, and elucidate how the processes of nuclear import and chromatin assembly are coordinated. Every cell cycle the entire DNA content of a cell must be rapidly replicated and repackaged into nucleosomes. Histones are proposed to follow a specific and highly regulated process of cytoplasmic post-translational modification, nuclear import and delivery, followed by assembly into chromatin. This project focuses on the significant question of whether nuclear import factors regulate processes beyond import, such as the intranuclear delivery and assembly of histone complexes. In addition, it will test whether histone modifying enzymes and chromatin assembly factors regulate nuclear import, providing a co-ordinate link between these processes. Specifically, the cytoplasmic post translational modifications of yeast histones will be identified and their importance in the regulation of import examined. The hypothesis is that modification of histones in the cytoplasm plays a regulatory role in transport by affecting association of histones with specific transport factors. The role of the nucleosome assembly protein (Nap1p) in histone import will be tested to determine whether this protein facilitates the association of histones H2A and H2B with a specific import factor. The requirements for the RanGTP-mediated dissociation of histones from their cognate import factors will be investigated. The hypothesis will be tested that the dissociation of histones from the Kaps is regulated by post-translational modifications and chromatin assembly factors. This may be a mechanism to regulate the spatial and temporal delivery of histones to chromatin assembly factors at the replication fork. The correct assembly of nucleosomes is critical for maintaining genomic stability in all eukaryotic cells. The dysfunction of proteins involved in the nucleosome assembly and remodeling pathways is also coincident with human disease and cancer. This highlights the fundamental importance of understanding the mechanisms by which histones are imported into the nucleus and assembled into chromatin, and how these processes are coordinated.