Identifying Conserved Amino Acids in Human Papillomavirus E7 Associated With Oncogenic Types Versus Non-Oncogenic Types

Abstract

Human papillomavirus (HPV) is a double-stranded DNA virus that infects both cutaneous and mucosal tissue. Although the majority of human papillomaviruses are non-oncogenic, some have been linked to cancers such as cervical, anogenital, and oropharyngeal cancer. HPV codes for two oncogenes, E6 and E7. E7 inhibits pRb by binding with its LXCXE motif, releasing E2F and forcing the cell into S phase with the goal of priming the cell for viral replication. Oncogenic and non-oncogenic HPV E7 proteins differ in how they interact with pRb; E7 from oncogenic HPVs bind to pRb with a higher affinity and target it for degradation, unlike non-oncogenic HPV E7. This leads to the hypothesis that there may be key residues that differ in conservation between oncogenic and non-oncogenic HPVs that contribute to their difference in oncogenicity. These residues may be located within or adjacent to the binding motif for pRb, LXCXE, or in other regions of the E7 protein. Three residues within HPV E7 were identified that were conserved exclusively among oncogenic HPVs and HPVs considered to be probably or possibly oncogenic. One of these residues, an aspartic acid upstream of the LXCXE motif, has been shown to be important for transformation through mutagenic studies. The second residue identified was a tyrosine at the second variable position of LXCXE, and the third was a cysteine at the first variable position of the first of two CXXC motifs that make up the zinc-finger domain of E7. All three of these residues were predicted to be conserved in the most recent common ancestor of the Alphapapillomavirus genus, which is suspected to be non-oncogenic based on phylogenetic parsimony. This suggests that these three conserved residues, which are conserved in oncogenic HPVs but also their possibly non-oncogenic ancestors, are not sufficient to explain the oncogenicity of certain HPVs. However, these residues may be enabling factors for oncogenicity, based on the importance of one of the residues for transformation shown in several experimental studies.