Vaccinia Virus Arrests and Shifts the Cell Cycle.

Caroline K Martin,Cosetta Bertoli,Annabel T Olson,Matthew S Wiebe,Jason Mercer,Robertus A M De Bruin,Jerzy Samolej

doi:10.3390/v14020431

Abstract

Modulation of the host cell cycle is a common strategy used by viruses to create a pro-replicative environment. To facilitate viral genome replication, vaccinia virus (VACV) has been reported to alter cell cycle regulation and trigger the host cell DNA damage response. However, the cellular factors and viral effectors that mediate these changes remain unknown. Here, we set out to investigate the effect of VACV infection on cell proliferation and host cell cycle progression. Using a subset of VACV mutants, we characterise the stage of infection required for inhibition of cell proliferation and define the viral effectors required to dysregulate the host cell cycle. Consistent with previous studies, we show that VACV inhibits and subsequently shifts the host cell cycle. We demonstrate that these two phenomena are independent of one another, with viral early genes being responsible for cell cycle inhibition, and post-replicative viral gene(s) responsible for the cell cycle shift. Extending previous findings, we show that the viral kinase F10 is required to activate the DNA damage checkpoint and that the viral B1 kinase and/or B12 pseudokinase mediate degradation of checkpoint effectors p53 and p21 during infection. We conclude that VACV modulates host cell proliferation and host cell cycle progression through temporal expression of multiple VACV effector proteins. (209/200.)

Highlights

The cell cycle is the most fundamental molecular process of all life forms, orchestrating consecutive phases of cell growth (G1), DNA replication (S), DNA proofreading (G2), and cell division [1]
We show that vaccinia virus (VACV) B1 and/or B12 mediates degradation of checkpoint effectors p53 and p21 to facilitate the cell cycle shift followed by DNA damage checkpoint activation by the viral kinase F10 [25–27,34]
We investigated the impact of VACV infection on the host cell cycle in cancer cells

Summary

Introduction

The cell cycle is the most fundamental molecular process of all life forms, orchestrating consecutive phases of cell growth (G1), DNA replication (S), DNA proofreading (G2), and cell division (mitosis, M) [1]. Cell cycle progression, or movement through the various stages of the cell cycle, is driven by cyclin-dependent kinases (CDKs) and their specific activators, cyclins, while specialised molecular checkpoints ensure correct completion of each phase [1–11]. If a problem occurs during replication, such as DNA damage, checkpoint activation serves to pause the cell cycle and repair the damage or, if not possible, to induce apoptosis [2,4,12,13]. By dysregulating cell cycle checkpoints—to arrest or induce cell cycle progression—many viruses modify the cell environment to promote viral genome replication, protein production and the assembly of progeny virions [14,15]

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Conclusion