Can Canine Papillomavirus Be Oncogenic in Humans? A Bioinformatics Assessment of E6 Oncoprotein–p53 Interaction Across Host Species

Background: Papillomaviruses are typically host-specific and non-zoonotic, but sporadic reports suggest possible canine papillomavirus transmission to humans. This raises the question: could canine papillomavirus exert oncogenic effects in humans? The E6 oncoprotein promotes carcinogenesis by degrading the tumour suppressor p53. Whether canine E6 can interact with human p53 is unknown.

Objectives: To evaluate the potential oncogenicity of canine papillomavirus E6 oncoprotein in humans through comparative sequence analysis, structural prediction, and molecular docking with human p53.

Methods: E6 sequences from human and canine papillomaviruses were retrieved from NCBI. Phylogenetic analysis (MEGA) identified closest human–canine E6 pairs. Three-dimensional structures were predicted with ColabFold and refined with PyMOL. Molecular docking against human p53 chain A was performed using HawkDock. Binding free energy (ΔG) and residue-level interactions were analysed for the top three models.

Results: Human and canine E6 protein sequences shared <30%amino acid similarity. Canine E6 was shorter and lacked one functional motif. Docking revealed ΔG = −52 kJ/mol for human E6–human p53 versus ΔG = −36 kJ/mol for canine E6–human p53, indicating weaker binding. In human E6, 48% of human p53 binding sites mapped to p53 residues 100–140; in canine E6, 39% mapped to residues 150–200, with no binding sites in the 100–140 region, suggesting a distinct and likely less effective interface.

Conclusions: While a ΔG of −36 kJ/mol indicates measurable binding between canine E6 and human p53, the substantially reduced binding affinity, low sequence similarity, absence of a key functional motif, and altered p53 binding site distribution collectively suggest that canine papillomavirus E6 oncoprotein is unlikely to exert significant oncogenic activity in humans through the p53 degradation pathway. However, alternative oncogenic mechanisms cannot be excluded. Further in vitro and in vivo investigations are warranted to fully characterise the zoonotic oncogenic potential of canine papillomavirus.