: Bovine Papillomavirus (BPV) is a member of a large family of closely related viruses that give rise to warts in their hosts. Infection of the genital tract by the human viruses from this group represents one of the few firmly established links between viral infection and the development of cervical cancer. Although the progression to malignancy represents a low frequency event, due to the high frequency of infection, this disease affects a large number of individuals. BPV has served as a prototype for this group especially regarding viral DNA replication. The El protein belongs to a family of multifunctional viral proteins whose main function is related to viral DNA replication. These proteins bind to the origin of DNA replication, and also have other activities related to DNA replication including a DNA distortion and a DNA helicase activity. Furthermore, these proteins interact with cellular replication proteins such as DNA pol alpha and RPA. Thus, this group of proteins are intimately involved with initiation of DNA replication. The objectives of this proposal are to provide high resolution structural information about the BPV El initiator protein and its DNA binding activity. The information gained from this study will be relevant in two areas: The first is to provide general insight into the biochemical events that are involved in viral DNA replication. This, in turn, can provide a basis for the development of clinical intervention strategies. Secondly, the viral DNA replication machinery itself represents an obvious target for antiviral therapy and detailed information such as high resolution structures of viral proteins required for replication will greatly facilitate the development and testing of antiviral agents.
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