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.
| Tarumoto, Yusuke; Lu, Bin; Somerville, Tim D D et al. (2018) LKB1, Salt-Inducible Kinases, and MEF2C Are Linked Dependencies in Acute Myeloid Leukemia. Mol Cell 69:1017-1027.e6 |
| Xu, Yali; Milazzo, Joseph P; Somerville, Tim D D et al. (2018) A TFIID-SAGA Perturbation that Targets MYB and Suppresses Acute Myeloid Leukemia. Cancer Cell 33:13-28.e8 |
| Huang, Yu-Han; Klingbeil, Olaf; He, Xue-Yan et al. (2018) POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer. Genes Dev 32:915-928 |
| Livshits, Geulah; Alonso-Curbelo, Direna; Morris 4th, John P et al. (2018) Arid1a restrains Kras-dependent changes in acinar cell identity. Elife 7: |
| Tiriac, Hervé; Belleau, Pascal; Engle, Dannielle D et al. (2018) Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer. Cancer Discov 8:1112-1129 |
| Bhagwat, Anand S; Lu, Bin; Vakoc, Christopher R (2018) Enhancer dysfunction in leukemia. Blood 131:1795-1804 |
| Banito, Ana; Li, Xiang; Laporte, Aimée N et al. (2018) The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma. Cancer Cell 34:346-348 |
| Skucha, Anna; Ebner, Jessica; Schmöllerl, Johannes et al. (2018) MLL-fusion-driven leukemia requires SETD2 to safeguard genomic integrity. Nat Commun 9:1983 |
| Banito, Ana; Li, Xiang; Laporte, Aimée N et al. (2018) The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma. Cancer Cell 33:527-541.e8 |
| Lin, Kuan-Ting; Ma, Wai Kit; Scharner, Juergen et al. (2018) A human-specific switch of alternatively spliced AFMID isoforms contributes to TP53 mutations and tumor recurrence in hepatocellular carcinoma. Genome Res : |
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