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Journal of Virology, November 2002, p. 11350-11358, Vol. 76, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.22.11350-11358.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Regulation of Bovine Papillomavirus Replicative Helicase E1 by the Ubiquitin-Proteasome Pathway

Marie-Helene Malcles, Nathalie Cueille,{dagger} Francisca Mechali, Olivier Coux, and Catherine Bonne-Andrea*

Centre de Recherches de Biochimie Macromoléculaire, CNRS, IFR 24, 34 293 Montpellier Cedex 5, France

Received 1 May 2002/ Accepted 13 August 2002

Papillomaviruses maintain their genomes in a relatively constant copy number as stable extrachromosomal plasmids in the nuclei of dividing host cells. The viral initiator of replication, E1, is not detected in papillomavirus-infected cells. Here, we present evidence that E1 encoded by bovine papillomavirus type 1 is an unstable protein that is degraded through the ubiquitin-proteasome pathway. In a cell-free system derived from Xenopus egg extracts, E1 degradation is regulated by both cyclin E/Cdk2 binding and E1 replication activity. Free E1 is readily ubiquitinated and degraded by the proteasome, while it becomes resistant to this degradation pathway when bound to cyclin E/Cdk2 complexes before the start of DNA synthesis. This stabilization is reversed in a process involving E1-dependent replication activity. In transiently transfected cells, E1 is also polyubiquitinated and accumulates when proteasome activity is inhibited. Thus, the establishment and maintenance of a stable number of papillomavirus genomes in latently infected cells are in part a function of regulated ubiquitin-mediated degradation of E1.

* Corresponding author. Mailing address: Centre de Recherches de Biochimie Macromoléculaire, CNRS, IFR 24, 1919 Route de Mende, 34 293 Montpellier Cedex 5, France. Phone: 33 4 67 61 33 32. Fax: 33 4 67 52 15 59. E-mail: bonne-andrea{at}crbm.cnrs-mop.fr.

{dagger} Present address: Swiss Institute for Experimental Cancer Research, CH-1066 Epalinges/Lausanne, Switzerland.

Journal of Virology, November 2002, p. 11350-11358, Vol. 76, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.22.11350-11358.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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