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Journal of Virology, December 2007, p. 13265-13270, Vol. 81, No. 23
0022-538X/07/$08.00+0     doi:10.1128/JVI.01121-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Human Papillomavirus Type 16 E7 Oncoprotein Activates the Fanconi Anemia (FA) Pathway and Causes Accelerated Chromosomal Instability in FA Cells{triangledown}

Nicole Spardy,1,2 Anette Duensing,2,3 Domonique Charles,2 Nathan Haines,2 Tomomi Nakahara,4 Paul F. Lambert,4 and Stefan Duensing2,5*

Biochemistry and Molecular Genetics Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261,1 Molecular Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213,2 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261,3 McArdle Laboratory for Cancer Research, University of Wisconsin—Madison, School of Medicine and Public Health, Madison, Wisconsin 53706,4 Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 152615

Received 23 May 2007/ Accepted 13 September 2007

Fanconi anemia (FA) patients have an increased risk for squamous cell carcinomas (SCCs) at sites of predilection for infection with high-risk human papillomavirus (HPV) types, including the oral cavity and the anogenital tract. We show here that activation of the FA pathway is a frequent event in cervical SCCs. We found that FA pathway activation is triggered mainly by the HPV type 16 (HPV-16) E7 oncoprotein and is associated with an enhanced formation of large FANCD2 foci and recruitment of FANCD2 as well as FANCD1/BRCA2 to chromatin. Episomal expression of HPV-16 oncoproteins was sufficient to activate the FA pathway. Importantly, the expression of HPV-16 E7 in FA-deficient cells led to accelerated chromosomal instability. Taken together, our findings establish the FA pathway as an early host cell response to high-risk HPV infection and may help to explain the greatly enhanced susceptibility of FA patients to squamous cell carcinogenesis at anatomic sites that are frequently infected by high-risk HPVs.

* Corresponding author. Mailing address: Molecular Virology Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Research Pavilion Suite 1.8, 5117 Centre Avenue, Pittsburgh, PA 15213. Phone: (412) 623-7719. Fax: (412) 623-7715. E-mail: duensing{at}pitt.edu

{triangledown} Published ahead of print on 26 September 2007.

Journal of Virology, December 2007, p. 13265-13270, Vol. 81, No. 23
0022-538X/07/$08.00+0     doi:10.1128/JVI.01121-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Spardy, N., Covella, K., Cha, E., Hoskins, E. E., Wells, S. I., Duensing, A., Duensing, S. (2009). Human Papillomavirus 16 E7 Oncoprotein Attenuates DNA Damage Checkpoint Control by Increasing the Proteolytic Turnover of Claspin. Cancer Res. 69: 7022-7029 [Abstract] [Full Text]  
  • Spardy, N., Duensing, A., Hoskins, E. E., Wells, S. I., Duensing, S. (2008). HPV-16 E7 Reveals a Link between DNA Replication Stress, Fanconi Anemia D2 Protein, and Alternative Lengthening of Telomere-Associated Promyelocytic Leukemia Bodies. Cancer Res. 68: 9954-9963 [Abstract] [Full Text]  
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  • Castle, P. E., Meyers, C., Alam, S., Conway, M. J. (2008). How Does Tobacco Smoke Contribute to Cervical Carcinogenesis?. J. Virol. 82: 6084-6086 [Full Text]  


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