One of the hallmarks of cancer cells is rapid, uncontrolled cellular proliferation. Understanding the molecular mechanisms involved in normal cell division is a major step toward understanding how these mechanisms are perturbed in cancer cells. The molecular controls that govern cell division are themselves regulated in the presence of DNA damage, halting cell division so damage can be repaired before potentially cancer-causing mutations are fixed in the cell. As part of a study designed to identify genes and proteins involved in regulating the cell cycle, we have identified three genes in the filamentous fungus Aspergillus nidulans, snxA, snxB, and snxC, which interact with the NIMXCDC2 protein. NIMXCDC2 is the A. nidulans ortholog of CDC2, which controls mitotic entry in all eukaryotes and is regulated in response to DNA damage. Mutations in the snx genes affect different aspects of the A. nidulans life cycle as well as interacting with NIMXCDC2, and preliminary evidence suggests that each may be involved in the DNA damage checkpoint pathway. The objectives of this proposal are to characterize the effects of the snxB1 and snxC1 mutations on the cell cycle and determine their involvement in the DNA damage checkpoint; to clone and sequence snxB; to clone and sequence snxA; and to design cell-based, protein-based, and gene expression assays applicable to the A. nidulans system using the Agilent 2100 Bioanalyzer. These experiments will provide new information on the molecular mechanisms involved in normal cell division and the DNA damage response, and may therefore impact the study of diseases of cell proliferation, such as cancer.
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