An interaction between human papillomavirus 16 E2 and TopBP1is required for optimum viral DNA replication and episomal genome establishment

Donaldson, M.M. , Mackintosh, L.J., Bodily, J.M., Dornan, E.S., Laimins, L.A. and Morgan, I.M. (2012) An interaction between human papillomavirus 16 E2 and TopBP1is required for optimum viral DNA replication and episomal genome establishment. Journal of Virology, 86(23), pp. 12806-12815. (doi:10.1128/JVI.01002-12)

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Abstract

In human papillomavirus DNA replication the viral protein E2 forms homodimers and binds to 12bp palindromic DNA sequences surrounding the origin of DNA replication. Via a protein-protein interaction it then recruits the viral helicase E1 to an A/T rich origin of replication whereupon a di-hexamer forms resulting in DNA replication initiation. In order to carry out DNA replication the viral proteins must interact with host factors that are currently not all known. An attractive cellular candidate for regulating viral replication is TopBP1, a known interactor of the E2 protein. In mammalian DNA replication TopBP1 loads DNA polymerases onto the replicative helicase following the G1 to S transition and this process is tightly cell cycle controlled. The direct interaction between E2 and TopBP1 would allow E2 to by-pass this cell cycle control resulting in DNA replication more than once per cell cycle which is a requirement for the viral life cycle. Here we report the generation of an HPV16 E2 mutant compromised in TopBP1 interaction in vivo and demonstrate that this mutant retains transcriptional activation and repression functions but has sub-optimal DNA replication potential. Introduction of this mutant into a viral life cycle model results in the failure to establish viral episomes. The results present a potential new anti-viral target, the E2-TopBP1 interaction, and increase our understanding of the viral life cycle suggesting that the E2-TopBP1 interaction is essential.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Donaldson, Dr Mary and Morgan, Professor Iain and Dornan, Mr Edward and Mackintosh, Dr Lorna
Authors: Donaldson, M.M., Mackintosh, L.J., Bodily, J.M., Dornan, E.S., Laimins, L.A., and Morgan, I.M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Clinical Specialities
Journal Name:Journal of Virology
Journal Abbr.:J. Virol.
Publisher:American Society fo Microbiology
ISSN:0022-538X
ISSN (Online):1098-5514
Published Online:12 September 2012

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