title: The fanconi anemia pathway limits human papillomavirus replication.
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.
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Hoskins
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Morreale
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Werner
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Higginbotham
authors.forename: Laimonis A
authors.initials: LA
authors.lastname: Laimins
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lambert
authors.forename: Darron R
authors.initials: DR
authors.lastname: Brown
authors.forename: Maura L
authors.initials: ML
authors.lastname: Gillison
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Nuovo
authors.forename: David P
authors.initials: DP
authors.lastname: Witte
authors.forename: Mi-Ok
authors.initials: MO
authors.lastname: Kim
authors.forename: Stella M
authors.initials: SM
authors.lastname: Davies
authors.forename: Parinda A
authors.initials: PA
authors.lastname: Mehta
authors.forename: Melinda
authors.initials: M
authors.lastname: Butsch Kovacic
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Wikenheiser-Brokamp
authors.forename: Susanne I
authors.initials: SI
authors.lastname: Wells
mesh_terms: D001938:Brazil / Q000453:epidemiology; D002294:Carcinoma, Squamous Cell / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002461:Cell Line, Transformed; D005199:Fanconi Anemia / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics / Q000378:metabolism*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism*; D005260:Female; D016679:Genome, Viral / Q000502:physiology*; D006258:Head and Neck Neoplasms / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology; D052162:Human papillomavirus 16 / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism*; D030361:Papillomavirus Infections / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014779:Virus Replication / Q000502:physiology*
chemical_list: C498471:FANCA protein, human; C499905:FANCD2 protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16