title: HPV16-E2 induces prophase arrest and activates the cellular DNA damage response in vitro and in precursor lesions of cervical carcinoma.
abstract: Cervical intraepithelial neoplasia (CIN) is caused by human papillomavirus (HPV) infection and is the precursor to cervical carcinoma. The completion of the HPV productive life cycle depends on the expression of viral proteins which further determines the severity of the cervical neoplasia. Initiation of the viral productive replication requires expression of the E2 viral protein that cooperates with the E1 viral DNA helicase. A decrease in the viral DNA replication ability and increase in the severity of cervical neoplasia is accompanied by simultaneous elevated expression of E6 and E7 oncoproteins. Here we reveal a novel and important role for the HPV16-E2 protein in controlling host cell cycle during malignant transformation. We showed that cells expressing HPV16-E2 in vitro are arrested in prophase alongside activation of a sustained DDR signal. We uncovered evidence that HPV16-E2 protein is present in vivo in cells that express both mitotic and DDR signals specifically in CIN3 lesions, immediate precursors of cancer, suggesting that E2 may be one of the drivers of genomic instability and carcinogenesis in vivo.
authors.affiliation: Institute of Medical Biology, A*STAR, Singapore.|Current address: p53 Laboratory, A*STAR, Singapore.
authors.forename: Yuezhen
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Institute of Medical Biology, A*STAR, Singapore.
authors.forename: Shen Yon
authors.initials: SY
authors.lastname: Toh
authors.affiliation: Institute of Medical Biology, A*STAR, Singapore.
authors.forename: Pingping
authors.initials: P
authors.lastname: He
authors.affiliation: Department of Gynaecological Oncology, KK Women's and Children's Hospital, Singapore.
authors.forename: Thimothy
authors.initials: T
authors.lastname: Lim
authors.affiliation: Department of Pathology, National University Hospital, Singapore.
authors.forename: Diana
authors.initials: D
authors.lastname: Lim
authors.affiliation: Singapore Immunology Network, A*STAR, Singapore.
authors.forename: Chai Ling
authors.initials: CL
authors.lastname: Pang
authors.affiliation: Singapore Immunology Network, A*STAR, Singapore.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Abastado
authors.affiliation: Institute of Medical Biology, A*STAR, Singapore.
authors.forename: Françoise
authors.initials: F
authors.lastname: Thierry
mesh_terms: D015153:Blotting, Western; D059447:Cell Cycle Checkpoints; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D030361:Papillomavirus Infections / Q000150:complications / Q000821:virology; D011230:Precancerous Conditions / Q000473:pathology / Q000821:virology*; D011418:Prophase; D002583:Uterine Cervical Neoplasms / Q000473:pathology / Q000821:virology*; D002578:Uterine Cervical Dysplasia / Q000473:pathology / Q000821:virology*
chemical_list: D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral
keywords: DNA damage response; HPV16-E2; cell cycle; cervical intraepithelial neoplasia; prophase