Abstract
The differences between high risk and low risk human papillomaviruses (HR-HPV and LR-HPV, respectively) that contribute to the tumorigenic potential of HR-HPV are not well understood but can be expected to involve the HPV oncoproteins, E6 and E7. We combine genome comparison and machine learning techniques to identify a previously unnoticed insert near the 3'-end of the E6 oncoprotein gene that is unique to HR-HPV. Analysis of the insert sequence suggests that it exerts a dual effect, by creating a PDZ domain-binding motif at the C-terminus of E6, as well as eliminating the overlap between the E6 and E7 coding regions in HR-HPV. We show that, as a result, the insert might enable coupled termination-reinitiation of the E6 and E7 genes, supported by motifs complementary to the human 18S rRNA. We hypothesize that the added functionality of E6 and positive regulation of E7 expression jointly account for the tumorigenic potential of HR-HPV.
Highlights
The differences between high risk and low risk human papillomaviruses (HR-Human papillomavirus (HPV) and LR-HPV, respectively) that contribute to the tumorigenic potential of HR-HPV are not well understood but can be expected to involve the HPV oncoproteins, E6 and E7
We revisited this problem by performing a search for genomic determinants of the oncogenic risk of alpha-HPV types and identified a unique insert in the 3’-terminal regions of the E6 oncoprotein genes in all HR-HPV strains
The insertion maintains closely similar lengths of E6 proteins in HR-HPV and LR-HPV types, which could explain why it has been overlooked in previous HPV genome analyses
Summary
The differences between high risk and low risk human papillomaviruses (HR-HPV and LR-HPV, respectively) that contribute to the tumorigenic potential of HR-HPV are not well understood but can be expected to involve the HPV oncoproteins, E6 and E7. We combine genome comparison and machine learning techniques to identify a previously unnoticed insert near the 3’-end of the E6 oncoprotein gene that is unique to HR-HPV. As a result, the insert might enable coupled termination-reinitiation of the E6 and E7 genes, supported by motifs complementary to the human 18S rRNA. We mention the most recent number of HPV types that have been formally recognized 198), and the reference supporting this has been updated. 2. We added numerous references to recent publications that describe analyses of HPV evolution, oncogenicity, oncoprotein interactions and E6 interactions with PDZ domains. We include all 64 alpha HPV types from PaVE, and all analyses and Figure 1– Figure 3 include those HPV strains
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