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Journal of Virology, May 2005, p. 5933-5942, Vol. 79, No. 10
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.10.5933-5942.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Identification of cis-Acting Elements That Mediate the Replication and Maintenance of Human Papillomavirus Type 16 Genomes in Saccharomyces cerevisiae

Kitai Kim ,^, Peter C. Angeletti,^, Elizabeth C. Hassebroek, and Paul F. Lambert^*

McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin

Received 10 October 2004/ Accepted 14 January 2005

Papillomaviruses contain small double-stranded DNA genomes that are maintained in persistently infected mammalian host epithelia as nuclear plasmids and rely upon the host replication machinery for replication. Papillomaviruses encode a DNA helicase, E1, which can specifically bind to the viral genome and support DNA synthesis. Under some conditions in mammalian cells, E1 is not required for viral DNA synthesis, leading to the hypothesis that papillomavirus DNA can be replicated solely by the host replication machinery. This machinery is highly conserved among eukaryotes. We and others found that papillomavirus DNA could replicate in a simple eukaryote, Saccharomyces cerevisiae. Specifically, papillomavirus DNA could substitute for the function of the autonomously replicating sequence (ARS) and centromere (CEN) elements that are normally both required for the stable replication of extrachromosomal DNAs in yeast. Furthermore, this form of replication in yeast was E1 independent. In this study, we map the elements in the human papillomavirus type 16 (HPV16) genome that can substitute for yeast ARS and CEN elements. A single element, termed rep, was identified that can substitute for ARS, and multiple elements, termed mtc, could substitute for CEN. The location of one of these mtc elements overlaps the location of rep, and this approximately 1,000-bp region of HPV16 was sufficient to support stable replication of a bacterial-yeast shuttle plasmid deleted of both ARS and CEN elements.

Kitai Kim and Peter C. Angeletti contributed equally to this paper.

Present address: Childrens Hospital, Harvard Medical School, New Research Building, 300 Longwood Ave., 7th floor, Boston, MA 02115.

Present address: Nebraska Center for Virology, E130 Beadle Center, University of Nebraska-Lincoln, 1901 Vine Street, Lincoln, NE 68588-0666.

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