Structure of origin DNA melting and unwinding complexes of a viral replication protein

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The papillomaviruses are an important class of disease causing organism in animals and man. Bovine papillomavirus (BPV-1) is the model of the group and the consequences of disease (interference with suckling, milking and breading), has a significant economic impact worldwide. The highly related human viruses (HPV) cause cancer and therefore also have a negative impact on quality of life. The mechanisms of viral replication are consequently of significant interest as the viral replication proteins are important therapeutic targets. The survival and continuity of an organism, be it a virus or man, requires duplication of its genetic material- its DNA- and this is performed by specialized proteins. The first important step in this process is the recognition of specific 'origins of DNA replication' by proteins that separate, or "melt", the two otherwise paired strands of the DNA ('the DNA double helix'). In higher organisms like man, the timing and physical precision of this 'initiation' event is crucial to avoid the catastrophic consequences that may result from any loss of genetic material (for example, cancer). After the initial melting of the DNA at localized site, complete separation of the two helical DNA strands is performed by 'helicase' proteins. DNA strand separation by initiator and helicase proteins is generally poorly understood in simple organisms like viruses as well as higher species like man. However, the process appears to be highly conserved, suggesting that mechanism may be generally similar in all systems. We propose here to explore and characterize these replication processes in BPV-1. The advantage is that all the viral DNA replication activities are performed by a single protein called E1, thus simplifying the study. We will use powerful microscopes to take snapshots of different steps of the process and biochemical techniques that will help to define mechanisms. These studies will therefore contribute significantly to the understanding of the papillomavirus replication protein that is an important therapeutic target. Modeling these replication events in this simplified viral system will also help us understand the process in man. These studies will therefore assist in disease management and improving human and animal health.