cellular function of Host Cell Factor (HCF). Human HCF (also termed C1, VCAF, and CFF) is a highly conserved nuclear protein that was first discovered as a result of its association with the herpes simplex virus (HSV) transactivator VP16 during HSV infection. Aside from its involvement in human viral infection, HCF has an important role in uninfected cells and its activity has been conserved in all metazoan species tested, including D. melanogaster and C. elegans. HCF has unusual structural properties. It is synthesized as a large 2035 amino-acid-long protein that is processed through proteolytic cleavage. Cleavage is directed by and occurs within a 26 amino acid sequence that is repeated six times near the center of HCF. Cleavage at these HCF repeats results in a heterogeneous set of similarly sized amino and carboxy terminal HCF fragments that remain associated with each other. Recently, HCF has been shown to be involved in cell proliferation. In a temperature sensitive hamster kidney cell line, a single amino acid substitution in HCF causes the arrest of cell proliferation at the nonpermissive temperature. This temperature sensitive HCF is also defective for interaction with VP16 and the cellular DNA binding leucine zipper protein (LZIP)- a putative cellular effector protein of HCF. In this project, the structure of HCF and its cellular functions will be dissected, focusing on HCF maturation though HCF repeat directed proteolysis, its role in cell proliferation and its functional interaction with other cellular proteins. Areas to be investigated are: (i) determine whether the subcellular localization of HCF or the association of amino and carboxy terminal HCF polypeptides are regulated during the cell cycle, (ii) identify the mechanisms by which HCF is proteolytically processed, (iii) determine the structure and function of HCF subdomains, (iv) identify the role of HCF in cell proliferation, and (v) elucidate the structure and function of HCF in heterologous organisms.
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