Abstract
The replication of human papillomavirus (HPV) genomes requires E1 and E2 proteins as the viral trans-factors and the replication origin, located in the URR, as a cis-element. The minimal requirements for an HPV replication origin vary among different virus types but always include one or more binding sites for the E2 protein. The requirements for an E1 binding site seem to vary among different HPV genera, with alpha-HPV11 and -18 minimal origins able to replicate without E1 binding site in contrast to beta-HPV8. In the present article, we analysed the sequence requirements for the beta-HPV5 minimal origin of replication. We show that the HPV5 URR is able to replicate in U2OS cells without the sequence proposed as an E1 binding site, albeit at lower levels than wt URR, given that three E2 binding sites are intact and both viral replication proteins are present. The lack of an absolute requirement of the E1 binding site for the origin of replication of HPV5 led us to analyse whether the viral E1 and E2 proteins from other HPV types are competent to support replication from this origin. Surprisingly, the E1 and E2 proteins from beta-HPV types support replication from the origin in contrast to proteins from alpha-HPV types 11, -16, or -18. Furthermore, the replication proteins E1 and E2 of these alpha-HPV types are unable to support the replication of HPV5 URR, even if the E1 binding site is intact. In light of these results, we performed a detailed analysis of the ability of different combinations of E1 and E2 proteins from various alpha- and beta-HPV types to support the replication of URR sequences from the respective HPV types in the U2OS cell line.
Highlights
Papillomaviruses (PVs) are widely spread oncogenic small DNA viruses that infect keratinocytes of cutaneous and mucosal epithelial tissues
We show that neither HPV5, HPV8 nor HPV38 Upstream Regulatory Region (URR) sequences replicate in the presence of alpha-papillomavirus E2 proteins, whereas replication of α-papillomavirus URRs occurs in the presence of β-PVs E2 proteins
Our results showed that HPV5 URR deletion construct (URR I) origin was able to replicate in the presence of HPV8 E1 and E2 proteins (Fig 3A, lanes 5–8), similar to HPV5 wt origin (Fig 3A, lanes 21–24)
Summary
Papillomaviruses (PVs) are widely spread oncogenic small DNA viruses that infect keratinocytes of cutaneous and mucosal epithelial tissues. More than 300 different papillomavirus types from humans (over 200 types) and other mammals, birds and reptiles have been described and completely sequenced to date Human papillomaviruses (HPVs) are divided into five genera: alpha-, beta, gamma-, mu-, and nu-papillomaviruses [2] [3]. The funder provided support in the form of salaries for authors [AL, MU, EU, MP], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section
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