This highlights the remarkable plasticity of hexameric structures

This highlights the remarkable plasticity of hexameric structures. Following recognition and binding to the origin of replication, melting of the DNA helix surrounding the origin, and oligomerization into two hexamers at the origin of replication, the LT-ag then recruits the cellular DNA replication factors: RPA, topoisomerase I and polymerase

α primase. Type I topoisomerases are essential to relieve supercoiling stress as the strands unwind (Lin et al., 2002). Podophyllotoxin (Condylox) is a topoisomerase I inhibitor in clinical use against HPV lesions to block DZNeP clinical trial viral DNA replication (Stern et al., 2012). As podophyllotoxin is also active against host chromosomal replication, it is cytotoxic. Following

the initiation events, the clamp loader, replication factor C (RFC), and the polymerase processivity factor, PCNA (proliferating cell nuclear antigen), are recruited and loaded leading to the binding and activity of DNA polymerase δ, which extends both lagging and leading strands. After PyV DNA replication and the expression of late structural proteins, new progeny virions Tyrosine Kinase Inhibitor Library cell assay are assembled and are released from the infected cell. Papillomaviruses are highly diverse and have been discovered in a wide array of vertebrates and their host range includes all amniotes (Rector and Van Ranst, 2013). Papillomaviruses are highly host-restricted, and cause abortive infections in non-host species. The HPV life cycle is closely linked to the differentiation state of the epithelial

cells and the initial step involves the infection of keratinocytes in the basal layer of squamous epithelia (Fig. 8) (Stanley, 2012, Carbohydrate Chow et al., 2010, Duensing and Munger, 2004 and zur Hausen, 2002). Similarly to PyVs, HPVs do not encode for their own DNA polymerases but they encode for viral proteins (i.e. E1 and E2) that are required for viral genome replication during the HPV productive cycle (Fig. 9A) (D’Abramo and Archambault, 2011, McBride, 2013 and Bergvall et al., 2013). E1 is the most highly conserved HPV protein and the only one with enzymatic activity. E1 is the replicative helicase of HPV and is essential for viral replication and pathogenesis. Both LT-ag and the E1 protein are structurally related members of the helicase superfamily III (SF3). E1 binds to the origin of replication together with E2 protein. In fact, the E2 protein assists and directs faithful viral origin recognition of E1 while E1 is the replicative DNA helicase, melting the DNA around the origin of replication and establishing itself as a double hexameric helicase. The formation of the E1–E2-origin of replication complex involves not only the binding of E1 and E2 to specific viral DNA elements in the origin of replication but also a protein–protein interaction between the N-terminal transactivation domain of E2 and the helicase/ATPase domain of E1 (Fig. 9B).

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