title: The human papillomavirus type 16 E7 oncoprotein activates the Fanconi anemia (FA) pathway and causes accelerated chromosomal instability in FA cells.
abstract: 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.
authors: Biochemistry and Molecular Genetics Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors: Nicole
authors: N
authors: Spardy
authors: Anette
authors: A
authors: Duensing
authors: Domonique
authors: D
authors: Charles
authors: Nathan
authors: N
authors: Haines
authors: Tomomi
authors: T
authors: Nakahara
authors: Paul F
authors: PF
authors: Lambert
authors: Stefan
authors: S
authors: Duensing
mesh_terms: D051017:Apoptosis Regulatory Proteins; D024682:BRCA2 Protein / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D043171:Chromosomal Instability; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism*; D052162:Human papillomavirus 16 / Q000378:metabolism*; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D011485:Protein Binding
chemical_list: D051017:Apoptosis Regulatory Proteins; C118024:BLID protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D002843:Chromatin; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16