This Article Full Text Full Text (PDF) 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 Hartley, K. A. Articles by Alexander, K. A. Search for Related Content PubMed PubMed Citation Articles by Hartley, K. A. Articles by Alexander, K. A.

 Previous Article  |  Next Article 

Journal of Virology, May 2002, p. 5014-5023, Vol. 76, No. 10
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.10.5014-5023.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Human TATA Binding Protein Inhibits Human Papillomavirus Type 11 DNA Replication by Antagonizing E1-E2 Protein Complex Formation on the Viral Origin of Replication

Department of Microbiology,¹ Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710²

Received 3 December 2001/ Accepted 18 February 2002

The human papillomavirus (HPV) protein E2 possesses dual roles in the viral life cycle. By interacting directly with host transcription factors in basal keratinocytes, E2 promotes viral transcription. As keratinocyte differentiation progresses, E2 associates with the viral helicase, E1, to activate vegetative viral DNA replication. How E2's major role switches from transcription to replication during keratinocyte differentiation is not understood, but the presence of a TATA site near the viral origin of replication led us to hypothesize that TATA-binding protein (TBP) could affect HPV replication. Here we show that the C-terminal domain of TBP (TBPc) is a potent inhibitor of E2-stimulated HPV DNA replication in vitro (50% inhibitory concentration = 0.56 nM). Increasing the E1 concentration could not overcome TBPc inhibition in replication assays, indicating that TBPc is a noncompetitive inhibitor of E1 binding. While direct E2-TBPc association could be demonstrated, this interaction could not fully account for the mechanism of TBPc-mediated inhibition of viral replication. Because E2 supports sequence-specific binding of E1 to the viral ori, we proposed that TBPc antagonizes E1-ori association indirectly through inhibition of E2-DNA binding. Indeed, TBPc potently antagonized E2 binding to DNA in the absence (K_i = 0.5 ± 0.1 nM) and presence (K_i = 0.6 ± 0.3 nM) of E1. Since E2 and TBPc cannot be coadjacent on viral sequences, direct DNA-binding competition between TBPc and E2 was responsible for replication inhibition. Given the ability of TBPc to inhibit HPV DNA replication in vitro and data indicating that TBPc antagonized E2-ori association, we propose that transcription factors regulate HPV DNA replication as well as viral transcription.

This article has been cited by other articles:

• Francois, A., Guilbaud, M., Awedikian, R., Chadeuf, G., Moullier, P., Salvetti, A. (2005). The Cellular TATA Binding Protein Is Required for Rep-Dependent Replication of a Minimal Adeno-Associated Virus Type 2 p5 Element. J. Virol. 79: 11082-11094 [Abstract] [Full Text]  
• Deng, S.-J., Pearce, K. H., Dixon, E. P., Hartley, K. A., Stanley, T. B., Lobe, D. C., Garvey, E. P., Kost, T. A., Petty, R. L., Rocque, W. J., Alexander, K. A., Underwood, M. R. (2004). Identification of Peptides That Inhibit the DNA Binding, trans-Activator, and DNA Replication Functions of the Human Papillomavirus Type 11 E2 Protein. J. Virol. 78: 2637-2641 [Abstract] [Full Text]  
• Hou, S. Y., Wu, S.-Y., Chiang, C.-M. (2002). Transcriptional Activity among High and Low Risk Human Papillomavirus E2 Proteins Correlates with E2 DNA Binding. J. Biol. Chem. 277: 45619-45629 [Abstract] [Full Text]  
• Quadt, I., Mainz, D., Mans, R., Kremer, A., Knebel-Morsdorf, D. (2002). Baculovirus Infection Raises the Level of TATA-Binding Protein That Colocalizes with Viral DNA Replication Sites. J. Virol. 76: 11123-11127 [Abstract] [Full Text]