title: Stranglehold on the spindle assembly checkpoint: the human papillomavirus E2 protein provokes BUBR1-dependent aneuploidy.
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.
authors: a Cell Cycle Control in Skin Epidermis; Institute of Medical Biology; A*Star, Biopolis ; Immunos , Singapore.
authors: Chye Ling
authors: CL
authors: Tan
authors: Sébastien
authors: S
authors: Teissier
authors: Jayantha
authors: J
authors: Gunaratne
authors: Ling Shih
authors: LS
authors: Quek
authors: Sophie
authors: S
authors: Bellanger
mesh_terms: D000782:Aneuploidy; D064199:Cdc20 Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D052161:Human papillomavirus 18 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000821:virology; D059566:M Phase Cell Cycle Checkpoints; D064246:Mad2 Proteins / Q000235:genetics / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D030361:Papillomavirus Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000821:virology
chemical_list: D064199:Cdc20 Proteins; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D009856:Oncogene Proteins, Viral; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C069102:oncogene protein E2, Human papillomavirus type 18; C577488:CDC20 protein, human; C584277:BUB1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: APC/C, Anaphase Promoting Complex/Cyclosome; Ad, Adenovirus; BUBR1; E2; E2 TAD, E2 Transactivation Domain; E2 ΔTAD, E2 deleted of the Transactivation Domain; GFP, Green Fluorescent Protein; HPV, Human Papillomavirus; MCC, Mitotic Checkpoint Complex; MS, Mass Spectrometry; Noco, Nocodazole; SAC, Spindle Assembly Checkpoint; Thym, Thymidine; aneuploidy; m.o.i., Multiplicity of Infection; mitosis; p53; papillomavirus; spindle assembly checkpoint