Human papillomavirus type 16 E7 oncoprotein inhibits the anaphase promoting complex/cyclosome activity by dysregulating EMI1 expression in mitosis

Yu, Yueyang; Münger, Karl

doi:10.1016/j.virol.2013.08.013

Cited by 15 publications

(17 citation statements)

References 64 publications

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“…It has been recently demonstrated that E7 engages both SAC-independent 28 and SAC-dependent 24 mechanisms to prevent APC/C-dependent degradation of cyclin A and cyclin B. In the latter article, www.tandfonline.com both MAD2 and BUBR1 were found highly expressed in E7-positive cells.…”

Section: Discussionmentioning

confidence: 90%

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

et al. 2015

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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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Section: Discussionmentioning

confidence: 90%

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

et al. 2015

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“…The HPV E7 protein inappropriately stimulates cell cycle progression in the epithelial mid-layer, while E6 perturbs the Scrib and Par complexes to expand the population of infected cells capable of replicating the viral DNA. Expression of E7 alone has been shown to induce the formation of aberrant spindle poles [61,62], while disruption of Dlg and the Par complex also perturbs mitotic spindle orientation [63,64], all of which contributes to enhanced symmetrical cell division, thus expanding the population of replicationcompetent cells and accounting for the disordered epithelium observed in viral lesions.…”

Section: Cell Polarity and The Hpv Life Cyclementioning

confidence: 99%

Upsetting the Balance: When Viruses Manipulate Cell Polarity Control

Thomas

Banks

2018

Journal of Molecular Biology

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The central importance of cell polarity control is emphasized by the frequency with which it is targeted by many diverse viruses. It is clear that in targeting key polarity control proteins, viruses affect not only host cell polarity, but also influence many cellular processes, including transcription, replication, and innate and acquired immunity. Examination of the interactions of different virus proteins with the cell and its polarity controls during the virus life cycles, and in virally-induced cell transformation shows ever more clearly how intimately all cellular processes are linked to the control of cell polarity.

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“…Another possibility is that E7 influences DDR factor protein stability through effects on protein degradation machinery. E7 has been shown to inhibit the anaphase promoting complex/cyclosome (APC/C) (Yu and Munger, 2013), a ubiquitin ligase complex involved in regulation of mitotic progression, as well as the DDR (de Boer et al, 2016). However, whether E7-mediated inhibition of this complex occurs in a manner dependent on the Rb binding domain is not known.…”

Section: Discussionmentioning

confidence: 99%

The Rb binding domain of HPV31 E7 is required to maintain high levels of DNA repair factors in infected cells

2017

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Human papillomaviruses (HPV) exhibit constitutive activation of ATM and ATR DNA damage response (DDR) pathways, which are required for productive viral replication. Expression of HPV31 E7 alone is sufficient to activate the DDR through an unknown mechanism. Here, we demonstrate that the E7 Rb binding domain is required to increase levels of many DDR proteins, including ATM, Chk2, Chk1, the MRN components MRE11, Rad50, and NBS1, as well as the homologous recombination repair proteins BRCA1 and Rad51. Interestingly, we have found that the increase in these DNA repair proteins does not occur solely at the level of transcription, but that E7 broadly increases the half-life of these DDR factors, a phenotype that is lost in the E7 Rb binding mutant. These data suggest that HPV-31 upregulates DNA repair factors necessary for replication by increasing protein half-life in a manner requiring the E7 Rb binding domain.

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Human papillomavirus type 16 E7 oncoprotein inhibits the anaphase promoting complex/cyclosome activity by dysregulating EMI1 expression in mitosis

Cited by 15 publications

References 64 publications

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

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

Upsetting the Balance: When Viruses Manipulate Cell Polarity Control

The Rb binding domain of HPV31 E7 is required to maintain high levels of DNA repair factors in infected cells

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