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    Mitotic control of human papillomavirus genome-containing cells is regulated by the function of the PDZ-binding motif of the E6 oncoprotein.

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    oncotarget-08-19491.pdf
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    Authors
    Marsh, Elizabeth K. cc
    Delury, Craig P.
    Davies, Nicholas J.
    Weston, Christopher J.
    Miah, Mohammed A. L.
    Banks, Lawrence
    Parish, Joanna L.
    Higgs, Martin R.
    Roberts, Sally
    Affiliation
    University of Birmingham
    International Centre for Genetic Engineering and Biotechnology
    Issue Date
    2017-01-03
    
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    Abstract
    The function of a conserved PDS95/DLG1/ZO1 (PDZ) binding motif (E6 PBM) at the C-termini of E6 oncoproteins of high-risk human papillomavirus (HPV) types contributes to the development of HPV-associated malignancies. Here, using a primary human keratinocyte-based model of the high-risk HPV18 life cycle, we identify a novel link between the E6 PBM and mitotic stability. In cultures containing a mutant genome in which the E6 PBM was deleted there was an increase in the frequency of abnormal mitoses, including multinucleation, compared to cells harboring the wild type HPV18 genome. The loss of the E6 PBM was associated with a significant increase in the frequency of mitotic spindle defects associated with anaphase and telophase. Furthermore, cells carrying this mutant genome had increased chromosome segregation defects and they also exhibited greater levels of genomic instability, as shown by an elevated level of centromere-positive micronuclei. In wild type HPV18 genome-containing organotypic cultures, the majority of mitotic cells reside in the suprabasal layers, in keeping with the hyperplastic morphology of the structures. However, in mutant genome-containing structures a greater proportion of mitotic cells were retained in the basal layer, which were often of undefined polarity, thus correlating with their reduced thickness. We conclude that the ability of E6 to target cellular PDZ proteins plays a critical role in maintaining mitotic stability of HPV infected cells, ensuring stable episome persistence and vegetative amplification.
    Citation
    Marsh, E. et al (2017) 'Mitotic control of human papillomavirus genome-containing cells is regulated by the function of the PDZ-binding motif of the E6 oncoprotein.', Oncotarget, 8 (12):19491-19506.
    Publisher
    Impact Journals
    Journal
    Oncotarget
    URI
    http://hdl.handle.net/10545/621853
    DOI
    10.18632/oncotarget.14469
    PubMed ID
    28061478
    Additional Links
    http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=14469
    Type
    Article
    Language
    en
    ISSN
    19492553
    ae974a485f413a2113503eed53cd6c53
    10.18632/oncotarget.14469
    Scopus Count
    Collections
    Human Sciences Research Centre

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