This Article Full Text Full Text (PDF) Other Versions of this Article: JVI.01170-06v1 81/1/384    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hsu, C.-Y. Articles by Bonne-Andrea, C. Search for Related Content PubMed PubMed Citation Articles by Hsu, C.-Y. Articles by Bonne-Andrea, C.

Nucleocytoplasmic Shuttling of Bovine Papillomavirus E1 Helicase Downregulates Viral DNA Replication in S Phase

Chiung-Yueh Hsu, Francisca Mechali, and Catherine Bonne-Andrea^*

Centre de Recherches de Biochimie Macromoléculaire, CNRS, FRE 2593, IFR122, 1919 Route de Mende, 34293 Montpellier Cedex 5, France

Received 6 June 2006/ Accepted 5 October 2006

The papillomavirus E1 protein is essential for the initiation of viral replication. We previously showed that the bovine papillomavirus E1 protein is unstable and becomes resistant to ubiquitin-mediated degradation when tightly bound to cyclin E-cyclin-dependent kinase 2 (Cdk2) before the start of DNA synthesis. However, neither the protection nor the targeted degradation of E1 appears to depend on its phosphorylation by Cdk. Here, we report that Cdk phosphorylation of E1 is also not a prerequisite for the initiation of viral DNA replication either in vitro or in vivo. Nevertheless, we found that phosphorylation of one Cdk site, Ser283, abrogates E1 replicative activity only in a cellular context. We show that this site-specific phosphorylation of E1 drives its export from the nucleus and promotes its continuous nucleocytoplasmic shuttling. In addition, we find that E1 shuttling occurs in S phase, when cyclin A-Cdk2 is activated. E1 interacts with the active cyclin A-Cdk2 complex and is phosphorylated on Ser283 by this kinase. These data suggest that the phosphorylation of E1 on Ser283 is a negative regulatory event that is involved in preventing the amplification of viral DNA during S phase. This finding reveals a novel facet of E1 regulation that could account for the variations of the viral replication capacity during different cell cycle phases, as well as in different stages of the viral cycle.

Published ahead of print on 11 October 2006.

Present address: Institute of Molecular Biology, Academia Sinica, 128 Academia Road, Nankang, Taipei 11529, Taiwan.

This article has been cited by other articles:

• Cote-Martin, A., Moody, C., Fradet-Turcotte, A., D'Abramo, C. M., Lehoux, M., Joubert, S., Poirier, G. G., Coulombe, B., Laimins, L. A., Archambault, J. (2008). Human Papillomavirus E1 Helicase Interacts with the WD Repeat Protein p80 To Promote Maintenance of the Viral Genome in Keratinocytes. J. Virol. 82: 1271-1283 [Abstract] [Full Text]  
• Yu, J.-H., Lin, B. Y., Deng, W., Broker, T. R., Chow, L. T. (2007). Mitogen-Activated Protein Kinases Activate the Nuclear Localization Sequence of Human Papillomavirus Type 11 E1 DNA Helicase To Promote Efficient Nuclear Import. J. Virol. 81: 5066-5078 [Abstract] [Full Text]