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

Hdl Handle:
http://hdl.handle.net/10545/621853
Title:
Mitotic control of human papillomavirus genome-containing cells is regulated by the function of the PDZ-binding motif of the E6 oncoprotein.
Authors:
Marsh, Elizabeth K.; Delury, Craig P.; Davies, Nicholas J.; Weston, Christopher J.; Miah, Mohammed A. L.; Banks, Lawrence; Parish, Joanna L.; Higgs, Martin R.; 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.
Affiliation:
University of Birmingham; International Centre for Genetic Engineering and Biotechnology
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
Issue Date:
3-Jan-2017
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
Sponsors:
This work was supported by grants from the Wellcome Trust (093450/Z/10/Z and 09345/B/10/Z) and Cancer Research UK (C427/A8049).
Appears in Collections:
Department of Natural Sciences

Full metadata record

DC FieldValue Language
dc.contributor.authorMarsh, Elizabeth K.en
dc.contributor.authorDelury, Craig P.en
dc.contributor.authorDavies, Nicholas J.en
dc.contributor.authorWeston, Christopher J.en
dc.contributor.authorMiah, Mohammed A. L.en
dc.contributor.authorBanks, Lawrenceen
dc.contributor.authorParish, Joanna L.en
dc.contributor.authorHiggs, Martin R.en
dc.contributor.authorRoberts, Sallyen
dc.date.accessioned2017-09-18T09:50:27Z-
dc.date.available2017-09-18T09:50:27Z-
dc.date.issued2017-01-03-
dc.identifier.citationMarsh, 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.en
dc.identifier.issn19492553-
dc.identifier.pmid28061478-
dc.identifier.doi10.18632/oncotarget.14469-
dc.identifier.urihttp://hdl.handle.net/10545/621853-
dc.description.abstractThe 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.en
dc.description.sponsorshipThis work was supported by grants from the Wellcome Trust (093450/Z/10/Z and 09345/B/10/Z) and Cancer Research UK (C427/A8049).en
dc.language.isoenen
dc.publisherImpact Journalsen
dc.relation.urlhttp://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=14469en
dc.rightsArchived with thanks to Oncotargeten
dc.subjectHuman papillomavirus (HPV)en
dc.subjectPDZ proteinsen
dc.subjectCell cycleen
dc.subjectMitosisen
dc.titleMitotic control of human papillomavirus genome-containing cells is regulated by the function of the PDZ-binding motif of the E6 oncoprotein.en
dc.typeArticleen
dc.contributor.departmentUniversity of Birminghamen
dc.contributor.departmentInternational Centre for Genetic Engineering and Biotechnologyen
dc.identifier.journalOncotargeten

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