The human papillomavirus type 16 E7 oncoprotein activates the Fanconi anemia (FA) pathway and causes accelerated chromosomal instability in FA cells.
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.
Spardy
Nicole
N
Biochemistry and Molecular Genetics Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Duensing
Anette
A
Charles
Domonique
D
Haines
Nathan
N
Nakahara
Tomomi
T
Lambert
Paul F
PF
Duensing
Stefan
S
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
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