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Vaccinia virus modulates the host cell cycle to promote infection

Martin, Caroline Katharina; (2019) Vaccinia virus modulates the host cell cycle to promote infection. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Vaccinia Virus (VACV) is well-known as the vaccine used for the eradication of smallpox. It serves as the model orthopox virus and has gained further clinical significance as an oncolytic virus. As a member of the poxvirus family, VACV is a double-stranded DNA virus that replicates exclusively in the cytoplasm of infected cells. Early research suggested that VACV alters the host cell cycle and inhibits cellular DNA synthesis. Later, VACV was described to modulate key cell cycle regulators during late timepoints of infection. However, the relevance of this cell cycle subversion to VACV replication and how it is achieved remains undefined. In this PhD project, I combined state of the art techniques with classical assays to determine the (viral) effector proteins, their mode of action, and the contribution of the host cell cycle to productive VACV infection. Using recombinant VACV strains, RNAi, biochemistry, and super-resolution microscopy, I demonstrate that VACV early gene expression inhibits cell proliferation after viral entry. Concurrently, the cellular CDK inhibitor p21 is upregulated, while the tumour suppressor p53 is targeted for degradation by the viral kinase B1 and/or its paralog pseudokinase B12. The second wave of viral gene expression shifts the cell cycle from G1 to S/G2/M, while still inhibiting cell proliferation. Additionally, the viral kinase F10 was shown to be necessary and sufficient to cause degradation of p21, and for activation of the cellular DNA damage response (DDR), a process known to be essential for viral DNA replication. By probing these cellular pathways with a small molecule inhibitor library I defined their requirement for the viral life cycle. Screening for defects in viral late gene expression, I found inhibition of Aurora Kinases, selected CDKs, ATR and Chk1/2 interferes with infection. Collectively, I demonstrate that VACV modulates cell cycle checkpoints and identify the viral kinases B1 and F10 as potential temporal controllers of the host cell cycle that serve to promote productive viral replication.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Vaccinia virus modulates the host cell cycle to promote infection
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10085745
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