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Journal of Virology, November 2008, p. 10724-10734, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00921-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Functional Mapping of the Human Papillomavirus Type 16 E1 Cistron{triangledown}

Michael J. Lace,1,2 James R. Anson,1 Lubomir P. Turek,1,2 and Thomas H. Haugen1,2*

Department of Pathology, Veterans Affairs Medical Center,1 The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 522422

Received 2 May 2008/ Accepted 16 August 2008

Replication of the double-stranded, circular human papillomavirus (HPV) genomes requires the viral DNA replicase E1. Here, we report an initial characterization of the E1 cistron of HPV type 16 (HPV-16), the most common oncogenic mucosal HPV type found in cervical and some head and neck cancers. The first step in HPV DNA replication is an initial burst of plasmid viral DNA amplification. Complementation assays between HPV-16 genomes carrying mutations in the early genes confirmed that the expression of E1 was necessary for initial HPV-16 plasmid synthesis. The major early HPV-16 promoter, P97, was dispensable for E1 production in the initial amplification because cis mutations inactivating P97 did not affect the trans complementation of E1– mutants. In contrast, E1 expression was abolished by cis mutations in the splice donor site at nucleotide (nt) 226, the splice acceptor site at nt 409, or a TATAA box at nt 7890. The mapping of 5' mRNA ends using rapid amplification of cDNA ends defined a promoter with a transcription start site at HPV-16 nt 14, P14. P14-initiated mRNA levels were low and required intact TATAA (7890). E1 expression required the HPV-16 keratinocyte-dependent enhancer, since cis mutations in its AP-2 and TEF-1 motifs abolished the ability of the mutant genomes to complement E1– genomes, and it was further modulated by origin-proximal and -distal binding sites for the viral E2 gene products. We conclude that P14-initiated E1 expression is critical for and limiting in the initial amplification of the HPV-16 genome.

* Corresponding author. Mailing address: Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242. Phone: (319) 338-0581, ext. 5516. Fax: (319) 339-7178. E-mail: thomas-haugen{at}uiowa.edu

{triangledown} Published ahead of print on 2 August 2008.

Journal of Virology, November 2008, p. 10724-10734, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00921-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lace, M. J., Anson, J. R., Klingelhutz, A. J., Lee, J. H., Bossler, A. D., Haugen, T. H., Turek, L. P. (2009). Human Papillomavirus (HPV) Type 18 Induces Extended Growth in Primary Human Cervical, Tonsillar, or Foreskin Keratinocytes More Effectively than Other High-Risk Mucosal HPVs. J. Virol. 83: 11784-11794 [Abstract] [Full Text]  
  • Lace, M. J., Yamakawa, Y., Ushikai, M., Anson, J. R., Haugen, T. H., Turek, L. P. (2009). Cellular factor YY1 downregulates the human papillomavirus 16 E6/E7 promoter, P97, in vivo and in vitro from a negative element overlapping the transcription-initiation site. J. Gen. Virol. 90: 2402-2412 [Abstract] [Full Text]  
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  • Lace, M. J., Anson, J. R., Thomas, G. S., Turek, L. P., Haugen, T. H. (2008). The E8{wedge}E2 Gene Product of Human Papillomavirus Type 16 Represses Early Transcription and Replication but Is Dispensable for Viral Plasmid Persistence in Keratinocytes. J. Virol. 82: 10841-10853 [Abstract] [Full Text]  


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