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G2/M cell cycle arrest in the life cycle of viruses - PubMed

  • ️Mon Jan 01 2007

Review

G2/M cell cycle arrest in the life cycle of viruses

Clare Davy et al. Virology. 2007.

Abstract

There is increasing evidence that viral infection, expression of viral protein or the presence of viral DNA causes the host cell cycle to arrest during G2/M. The mechanisms used by viruses to cause arrest vary widely; some involve the activation of the cellular pathways that induce arrest in response to DNA damage, while others use completely novel means. The analysis of virus-mediated arrest has not been proven easy, and in most cases the consequences of arrest for the virus life cycle are not well defined. However, a number of effects of arrest are being investigated and it will be interesting to see to what extent perturbation of the G2/M transition is involved in viral infections.

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Figures

Fig. 1
Fig. 1

G2/M events targeted by viruses. The upper panels illustrate aspects of normal progression through G2/M. The lower panels show the sites where viruses and viral proteins are observed to cause changes to events of the G2/M transition (but do not necessarily imply direct action at this place; the virus/viral protein may in fact be acting somewhere upstream). Abbreviations: AAV—adeno-associated virus; APC—anaphase promoting complex; BDV—Borna disease virus; CAV—chicken anemia virus; HPV—human papillomavirus; HSV1—herpes simplex virus type 1; JCV—JC polyomavirus; MAPK—mitogen-activated protein kinase; MMV—mice minute virus; ODV—occlusion-derived virus; PP2A—protein phosphatase 2A. Reovirus in this instance refers to serotype 3.

Fig. 2
Fig. 2

G2 Arrest during the human papillomavirus (HPV) life cycle. The expression patterns of key HPV proteins including E7, which drives cells into S phase, and E4, which arrests cells in G2/M, are shown as vertical arrows adjacent to diagrammatic representations of infected epithelium. The images represent a model of the HPV life cycle, and are based on data presented in Middleton et al. (2003) and Peh et al. (2002). Initial infection occurs in the basal cells (purple) and expression of the viral E1 and E2 proteins facilitates replication of the viral episome. As the cells divide and leave the basal layer, they would normally become quiescent and differentiate but following HPV infection they can re-enter the cell cycle as a result of E7 expression. As the cells are pushed towards the epithelial surface the levels of E1, E2 and E4 expression increase, and the high levels of E4 protein cause the cells to arrest in G2. The continued expression of E7 in cells arrested in G2/M is thought to create a pseudo-S phase state, which facilitates viral genome amplification rather than cell proliferation. Active genome amplification ceases following the downregulation of E7, E1 and E2, and upregulation of the viral capsid proteins (L1 and L2). The timing of viral gene expression varies between HPV16 and HPV1 lesions but G2 arrest and amplification of the viral genomes occurs where the expression of E4 coincides with the expression of E7. The 1E4 protein is proteolytically cleaved during differentiation with the N-terminally truncated 16-kDa form, in addition to the full-length 17-kDa form, appearing to play a role in causing G2 arrest. Although proteolytic cleavage of HPV16 E4 occurs during differentiation, it is the full-length gene product that is responsible for growth arrest in G2. The HPV16 E4 protein prevents the nuclear accumulation of Cdk1/cyclin B1 that is required for mitosis by binding to the complex and tethering it to cytoplasmic keratins. This is illustrated to the left of the figure.

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