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J. Virol. doi:10.1128/JVI.01170-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Nucleo-cytoplasmic shuttling of bovine papillomavirus E1 helicase down regulates viral DNA replication in S phase

Centre de Recherches de Biochimie Macromoléculaire, CNRS, FRE 2593, IFR122, 1919 route de Mende, 34 293 Montpellier Cedex 5, France

^* To whom correspondence should be addressed. Email: catherine.bonne-andrea{at}crbm.cnrs.fr.

	Abstract

The papillomavirus E1 protein is essential for 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/Cdk2 before the start of DNA synthesis. However, neither protection nor targeted degradation of E1 appear to depend on its phosphorylation by Cdk. Here, we report that Cdk phosphorylation of E1 is also not a prerequisite for initiation of viral DNA replication both in vitro and in vivo. Nevertheless, we find 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 nucleo-cytoplasmic 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 amplification of viral DNA during S phase. This finding reveals a novel facet of E1 regulation that could account for variations of the viral replication capacity during different cell cycle phases, as well as in different stages of the viral cycle.

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