High incidence of female reproductive tract cancers in FA-deficient HPV16-transgenic mice correlates with E7's induction of DNA damage response, an activity mediated by E7's inactivation of pocket proteins.

Published

Journal Article

Fanconi anemia (FA) is a rare genetic disorder caused by defects in a DNA damage repair system, the FA pathway. FA patients frequently develop squamous cell carcinoma (SCC) at sites that are associated with human papillomavirus (HPV)-driven cancer including the female reproductive tract. To assess experimentally whether FA deficiency increases susceptibility to HPV-associated cervical/vaginal cancer, we monitored cancer incidence in the female lower reproductive tract of FA-deficient mice expressing HPV16 oncogenes, E6 and/or E7. FA deficiency specifically increased the incidence of cancers in mice expressing E7; but this effect was not observed in mice just expressing E6. We also observed that E7, but not E6, induced DNA damage as scored by induction of γ-H2AX and 53BP1 (p53 binding protein 1) nuclear foci, and this induction was heightened in FA-deficient tissue. Finally, we discovered that this induction of DNA damage responses was recapitulated in mice deficient in expression of 'pocket' proteins, pRb, p107 and p130, which are established targets of E7. Our findings support the hypothesis that E7 induces cancer by causing DNA damage at least in part through the inactivation of pocket proteins. This hypothesis explains why a deficiency in DNA damage repair would increase susceptibility to E7-driven cancer.

Full Text

Duke Authors

Cited Authors

  • Park, JW; Shin, M-K; Lambert, PF

Published Date

  • June 26, 2014

Published In

Volume / Issue

  • 33 / 26

Start / End Page

  • 3383 - 3391

PubMed ID

  • 24013229

Pubmed Central ID

  • 24013229

Electronic International Standard Serial Number (EISSN)

  • 1476-5594

Digital Object Identifier (DOI)

  • 10.1038/onc.2013.327

Language

  • eng

Conference Location

  • England