Understanding the mechanism of DNA replication in human cells is a fundamental problem in biology and has direct relevance to cancer research. Towards this goal, the mechanism of DNA replication from the Simian Virus 40 (SV40) and the bovine papillomavirus (BPV) origins of DNA replication will be investigated. In addition, the mechanism and regulation of DNA replication-dependent chromatin assembly will also be studies. Using cell-free extracts prepared from human cells and either purified SV40 T antigen or the BPV E1 and E2 proteins, factors required for virus DNA replication and their mechanism of action will be studies. A cellular protein essential for BVP DNA replication, but not for SV40 DNA replication, will be purified and its functions characterized. The mechanism of DNA polymerase switching involving Replication Factor C and the proliferating cell nuclear antigen (PCNA) will also be investigated, as will the interaction of these proteins with the cell division cycle regulator, p21. These proteins also appear to function in repair of radiation damaged DNA and therefore, these studies will provide insight into the controls that coordinated DNA replication, DNA repair and cell cycle progression. Finally, the functions of chromatin assembly factor 1 (CAF1) and its role in DNA replication- dependent chromatin assembly will be determined. Other chromatin assembly factors cooperate with CAF1 to assemble nucleosomes onto replication DNA and these will be purified with the goal of establishing the replication-dependent assembling in vitro with purified proteins. The proposed studies will determine the mechanism of initiation and elongation of DNA replication and replication-coupled chromatin assembly, all important aspects of DNA metabolism in proliferating cells. These studies are directly relevant to the overall goals of the program project.
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