The fanconi anemia pathway limits human papillomavirus replication

Elizabeth E. Hoskins, Richard J. Morreale, Stephen P. Werner, Jennifer M. Higginbotham, Laimonis A. Laimins, Paul F. Lambert, Darron Brown, Maura L. Gillison, Gerard J. Nuovo, David P. Witte, Mi Ok Kim, Stella M. Davies, Parinda A. Mehta, Melinda Butsch Kovacic, Kathryn A. Wikenheiser-Brokamp, Susanne I. Wells

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

High-risk human papillomaviruses (HPVs) deregulate epidermal differentiation and cause anogenital and head and neck squamous cell carcinomas (SCCs). The E7 gene is considered the predominant viral oncogene and drives proliferation and genome instability. While the implementation of routine screens has greatly reduced the incidence of cervical cancers which are almost exclusively HPV positive, the proportion of HPV-positive head and neck SCCs is on the rise. High levels of HPV oncogene expression and genome load are linked to disease progression, but genetic risk factors that regulate oncogene abundance and/or genome amplification remain poorly understood. Fanconi anemia (FA) is a genome instability syndrome characterized at least in part by extreme susceptibility to SCCs. FA results from mutations in one of 15 genes in the FA pathway, whose protein products assemble in the nucleus and play important roles in DNA damage repair. We report here that loss of FA pathway components FANCA and FANCD2 stimulates E7 protein accumulation in human keratinocytes and causes increased epithelial proliferation and basal cell layer expansion in the HPV-positive epidermis. Additionally, FANCD2 loss stimulates HPV genome amplification in differentiating cells, demonstrating that the intact FA pathway functions to restrict the HPV life cycle. These findings raise the possibility that FA genes suppress HPV infection and disease and suggest possible mechanism(s) for reported associations of HPV with an FA cohort in Brazil and for allelic variation of FA genes with HPV persistence in the general population.

Original languageEnglish
Pages (from-to)8131-8138
Number of pages8
JournalJournal of Virology
Volume86
Issue number15
DOIs
StatePublished - 2012

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Fanconi Anemia
Papillomaviridae
oncogenes
squamous cell carcinoma
Oncogenes
genome
Genomic Instability
Genes
neck
Fanconi anemia
genes
Genome
Papillomavirus Infections
uterine cervical neoplasms
Human Genome
protein products
epidermis (animal)
keratinocytes
Life Cycle Stages
Keratinocytes

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Hoskins, E. E., Morreale, R. J., Werner, S. P., Higginbotham, J. M., Laimins, L. A., Lambert, P. F., ... Wells, S. I. (2012). The fanconi anemia pathway limits human papillomavirus replication. Journal of Virology, 86(15), 8131-8138. https://doi.org/10.1128/JVI.00408-12

The fanconi anemia pathway limits human papillomavirus replication. / Hoskins, Elizabeth E.; Morreale, Richard J.; Werner, Stephen P.; Higginbotham, Jennifer M.; Laimins, Laimonis A.; Lambert, Paul F.; Brown, Darron; Gillison, Maura L.; Nuovo, Gerard J.; Witte, David P.; Kim, Mi Ok; Davies, Stella M.; Mehta, Parinda A.; Kovacic, Melinda Butsch; Wikenheiser-Brokamp, Kathryn A.; Wells, Susanne I.

In: Journal of Virology, Vol. 86, No. 15, 2012, p. 8131-8138.

Research output: Contribution to journalArticle

Hoskins, EE, Morreale, RJ, Werner, SP, Higginbotham, JM, Laimins, LA, Lambert, PF, Brown, D, Gillison, ML, Nuovo, GJ, Witte, DP, Kim, MO, Davies, SM, Mehta, PA, Kovacic, MB, Wikenheiser-Brokamp, KA & Wells, SI 2012, 'The fanconi anemia pathway limits human papillomavirus replication', Journal of Virology, vol. 86, no. 15, pp. 8131-8138. https://doi.org/10.1128/JVI.00408-12
Hoskins EE, Morreale RJ, Werner SP, Higginbotham JM, Laimins LA, Lambert PF et al. The fanconi anemia pathway limits human papillomavirus replication. Journal of Virology. 2012;86(15):8131-8138. https://doi.org/10.1128/JVI.00408-12
Hoskins, Elizabeth E. ; Morreale, Richard J. ; Werner, Stephen P. ; Higginbotham, Jennifer M. ; Laimins, Laimonis A. ; Lambert, Paul F. ; Brown, Darron ; Gillison, Maura L. ; Nuovo, Gerard J. ; Witte, David P. ; Kim, Mi Ok ; Davies, Stella M. ; Mehta, Parinda A. ; Kovacic, Melinda Butsch ; Wikenheiser-Brokamp, Kathryn A. ; Wells, Susanne I. / The fanconi anemia pathway limits human papillomavirus replication. In: Journal of Virology. 2012 ; Vol. 86, No. 15. pp. 8131-8138.
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