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Compromised spindle assembly checkpoint due to altered expression of Ubch10 and Cdc20 in human papillomavirus type 16

Daksha Patel1, Dennis J McCance

  • 1Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom. d.patel@qub.ac.uk

Journal of Virology
|August 27, 2010
PubMed

Insights

Human papillomavirus (HPV) oncoproteins E6 and E7 enable cells with DNA damage to bypass cell cycle arrest. These HPV-infected cells can enter and exit mitosis, avoiding cell death and continuing to proliferate.

Area of Science:

  • Cell Biology
  • Virology
  • Molecular Biology

Background:

  • Human papillomavirus type 16 (HPV-16) E6 and E7 proteins disrupt cell cycle regulation.
  • Cells with DNA damage normally arrest in the G2/M phase to prevent replication errors.
  • HPV-16 E6/E7 expressing cells bypass DNA damage checkpoints, entering mitosis despite damage.

Purpose of the Study:

  • To elucidate the mechanism by which HPV-16 E6/E7 expressing cells enter and exit mitosis despite DNA damage.
  • To investigate the role of cell cycle regulators, specifically cyclin B and APC/C, in this bypass mechanism.

Main Methods:

  • Analysis of cell cycle progression in HPV-16 E6/E7 expressing cells with DNA damage.
  • Measurement of cyclin B levels and degradation.
  • Investigation of the anaphase-promoting complex/cyclosome (APC/C) components, including Ubch10 and Cdc20.
  • Examination of Cdc20 interactions with checkpoint proteins like BubR1.

Main Results:

  • HPV-16 E6/E7 expressing cells show elevated cyclin B levels, facilitating mitotic entry.
  • Cyclin B is efficiently degraded in these cells, enabling exit from mitosis and subsequent cell cycle progression.
  • Elevated levels of Ubch10 and Cdc20 contribute to proteasomal degradation of cyclin B via APC/C.
  • Cdc20, while complexed with BubR1 (indicating checkpoint activity), is also found free, suggesting APC/C activation and checkpoint slippage.

Conclusions:

  • HPV-16 E6/E7 proteins facilitate mitotic entry and exit in the presence of DNA damage by modulating cyclin B levels and APC/C activity.
  • The elevated Ubch10 and Cdc20 levels, along with partial release of Cdc20 from BubR1, are key to enabling cell cycle progression through checkpoints.
  • These findings reveal a critical mechanism by which HPV-16 contributes to genomic instability and potentially oncogenesis.

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