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

Journal article


Marsh, Elizabeth K., Delury, Craig P., Davies, Nicholas J., Weston, Christopher J., Miah, Mohammed A. L., Banks, Lawrence, Parish, Joanna L., Higgs, Martin R. and Roberts, Sally 2017. Mitotic control of human papillomavirus genome-containing cells is regulated by the function of the PDZ-binding motif of the E6 oncoprotein. Oncotarget. https://doi.org/10.18632/oncotarget.14469
AuthorsMarsh, Elizabeth K., Delury, Craig P., Davies, Nicholas J., Weston, Christopher J., Miah, Mohammed A. L., Banks, Lawrence, Parish, Joanna L., Higgs, Martin R. and Roberts, Sally
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.

KeywordsHuman papillomavirus (HPV); PDZ proteins; Cell cycle; Mitosis
Year2017
JournalOncotarget
PublisherImpact Journals
ISSN19492553
Digital Object Identifier (DOI)https://doi.org/10.18632/oncotarget.14469
Web address (URL)http://hdl.handle.net/10545/621853
hdl:10545/621853
Publication dates03 Jan 2017
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Deposited18 Sep 2017, 09:50
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Archived with thanks to Oncotarget

ContributorsUniversity of Birmingham and International Centre for Genetic Engineering and Biotechnology
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https://repository.derby.ac.uk/item/94yq1/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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