Stranglehold on the spindle assembly checkpoint: the human papillomavirus E2 protein provokes BUBR1-dependent aneuploidy

Cell Cycle
Chye Ling TanSophie Bellanger

Abstract

The Human Papillomavirus (HPV) E2 protein, which inhibits the E6 and E7 viral oncogenes, is believed to have anti-oncogenic properties. Here, we challenge this view and show that HPV-18 E2 over-activates the Spindle Assembly Checkpoint (SAC) and induces DNA breaks in mitosis followed by aneuploidy. This phenotype is associated with interaction of E2 with the Mitotic Checkpoint Complex (MCC) proteins Cdc20, MAD2 and BUBR1. While BUBR1 silencing rescues the mitotic phenotype induced by E2, p53 silencing or presence of E6/E7 (inactivating p53 and increasing BUBR1 levels respectively) both amplify it. This work pinpoints E2 as a key protein in the initiation of HPV-induced cervical cancer and identifies the SAC as a target for oncogenic pathogens. Moreover, our results suggest a role of p53 in regulating the mitotic process itself and highlight SAC over-activation in a p53-negative context as a highly pathogenic event.

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Citations

Jan 21, 2016·Traffic·Inci Aydin, Mario Schelhaas
Jun 28, 2016·Biochimica Et Biophysica Acta·Kozo Tanaka, Toru Hirota
Sep 14, 2018·PLoS Pathogens·Fengchao LangErle S Robertson
Jul 10, 2019·Annual Review of Virology·Tami L Coursey, Alison A McBride

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Methods Mentioned

BETA
flow cytometry
immunoprecipitation
co-immunoprecipitations
PCR
transfection
FCS
Assay

Software Mentioned

GeneGo
WinMDI
SILAC
SoftWoRx

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