Abstract
BackgroundHuman papillomavirus (HPV) DNA replication can be inhibited by the cellular tumour suppressor protein p53. However, the mechanism through which p53 inhibits viral replication and the role that this might play in the HPV life cycle are not known. The papillomavirus E2 protein is required for efficient HPV DNA replication and also regulates viral gene expression. E2 represses transcription of the HPV E6 and E7 oncogenes and can thereby modulate indirectly host cell proliferation and survival. In addition, the E2 protein from HPV 16 has been shown to bind p53 and to be capable of inducing apoptosis independently of E6 and E7.ResultsHere we use a panel of E2 mutants to confirm that mutations which block the induction of apoptosis via this E6/E7-independent pathway, have little or no effect on the induction of apoptosis by the E6/E7-dependent pathway. Although these mutations in E2 do not affect the ability of the protein to mediate HPV DNA replication, they do abrogate the repressive effects of p53 on the transcriptional activity of E2 and prevent the inhibition of E2-dependent HPV DNA replication by p53.ConclusionThese data suggest that p53 down-regulates HPV 16 DNA replication via the E2 protein.
Highlights
Human papillomavirus (HPV) DNA replication can be inhibited by the cellular tumour suppressor protein p53
These data suggest that p53 down-regulates HPV 16 DNA replication via the E2 protein
Mutagenesis of the HPV 16 E2 protein The C-terminal DNA-binding domain of the HPV 16 E2 protein is important for binding to p53; residues 339–351 are essential for the interaction while residues 307–339 play a contributory role [27]
Summary
Human papillomavirus (HPV) DNA replication can be inhibited by the cellular tumour suppressor protein p53. The papillomavirus E2 protein is required for efficient HPV DNA replication and regulates viral gene expression. Human papillomaviruses (HPVs) are non-enveloped, small double-stranded DNA tumour viruses that are strictly epitheliotropic, infecting cutaneous or mucosal epithelial cells typically of the anogenital tract, hands or feet [1,2]. Many HPV types infect the genital tract and these viruses can be separated into two groups based on their oncogenic potential: high-risk HPV and low-risk HPV [1,2]. HPV types in the high-risk group are associated with the development of cancers of the anogenital tract, whereas low-risk HPVs are associated with benign genital warts. High-risk HPVs have (page number not for citation purposes)
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