Papillomaviruses cause warts and malignancies, including cancer of the cervix. The E2 protein serves multiple essential functions: control of viral transcription, stimulation of E1 mediated DNA replication, and partitioning of viral episomes in mitosis. The goal of this proposal is to determine the mechanisms by which E2 acts in these fundamental viral and cellular pathways. This will be accomplished through identification of cellular factors that interact with the E2 activation domain. We have previously reported that E2 binds AMF- 1, a novel nuclear protein, and SMN, a protein involved in RNA processing. We propose that AMP-i mediates chromatin remodeling at the E2 dependent promoter and origin of replication through its association with p300. We hypothesize that through interaction with SMN, E2 may regulate viral RNA processing. In the first aim we will continue our studies to characterize the significance of these interactions in the viral reproductive cycle. In the second aim we continue the search for other cellular factors that interact with E2, both in mammalian cells and in S. cerevisiae, in which E2 is transcriptionally active. We have identified and partially characterized one candidate E2 interacting gene that functions to maintain chromosomal integrity during mitosis in yeast, and speculate that it may mediate viral episome segregation through its interaction with the amino terminus of E2. We show that E2 binds the human homologue of this gene and will determine the role of this interaction for E2 function. These investigations should result in greater and new understanding of the mechanisms that control viral gene expression, RNA processing, and replication of the viral genome.
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