HPV16-E2 induces prophase arrest and activates the cellular DNA damage response in vitro and in precursor lesions of cervical carcinoma
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Yuezhen Xue1,5, Shen Yon Toh1, Pingping He1, Thimothy Lim2, Diana Lim3, Chai Ling Pang4, Jean-Pierre Abastado4, Françoise Thierry1
1Institute of Medical Biology, A*STAR, Singapore
2Department of Gynaecological Oncology, KK Women's and Children's Hospital, Singapore
3Department of Pathology, National University Hospital, Singapore
4Singapore Immunology Network, A*STAR, Singapore
5Current address: p53 Laboratory, A*STAR, Singapore
Yuezhen Xue, e-mail: [email protected]
Keywords: HPV16-E2, DNA damage response, cell cycle, prophase, cervical intraepithelial neoplasia
Received: April 12, 2015 Accepted: October 01, 2015 Published: October 14, 2015
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.
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