Virus DNA Replication and the Host DNA Damage Response

Abstract

Viral DNA genomes have limited coding capacity and therefore harness cellular factors to facilitate replication of their genomes and generate progeny virions. Studies of viruses and how they interact with cellular processes have historically provided seminal insights into basic biology and disease mechanisms. The replicative life cycles of many DNA viruses have been shown to engage components of the host DNA damage and repair machinery. Viruses have evolved numerous strategies to navigate the cellular DNA damage response. By hijacking and manipulating cellular replication and repair processes, DNA viruses can selectively harness or abrogate distinct components of the cellular machinery to complete their life cycles. Here, we highlight consequences for viral replication and host genome integrity during the dynamic interactions between virus and host.

Replication Compartments of DNA Viruses in the Nucleus: Location, Location, Location

“…Many DNA viruses hijack cellular chromatin modifiers to regulate their own viral chromatin, as well as cellular chromatin [70][71][72]. Furthermore, many DNA viruses activate the DDR, leading to the phosphorylation of histone γH2AX, which is a key mediator of cellular chromatin remodeling and condensation during DNA repair [8][9][10]. In addition, some DNA viruses such as HPV and HAdV encode viral proteins that can manipulate cellular chromatin [70,[73][74][75].…”

“…However, these viruses must overcome several challenges to form VRCs successfully. Firstly, incoming genomes must avoid cellular intrinsic antiviral defenses and homeostatic regulatory pathways such as elements of the DNA damage response (DDR) that respond to the presence of foreign DNA and act to suppress viral gene expression [3][4][5][6][7][8][9][10]. Secondly, VRCs typically form at specific sites within the nucleus, suggesting that viral genomes need to be targeted to these sites in order to initiate VRC formation [6,11,12].…”

Topoisomerase 2β-dependent nuclear DNA damage shapes extracellular growth factor responses through AKT phosphorylation dynamics to control virus latency

“…While we establish that the DDR influences HSV-1 latency in neurons by regulating AKT, it exerts a different impact upon productive virus growth, which has been primarily investigated in nonneuronal cells. Following nuclear entry, the viral linear dsDNA genome, which contains nicks and gaps (Smith et al, 2014), triggers the host DDR (Weitzman and Fradet-Turcotte, 2018). To prevent viral genome silencing and suppress antiviral defenses, virus-encoded factors antagonize select DDR components (Lilley et al, 2011).…”

Rotavirus activates a noncanonical ATM‐Chk2 branch of DNA damage response during infection to positively regulate viroplasm dynamics

“…A simplistic view on this noncanonical occurrence holds that the chain of activation events from proximal to distal arm of DDR, which remains canonically unperturbed, becomes tampered with during viral infection leading to proximal activation getting uncoupled from distal effects Luftig, 2014;Pancholi et al, 2017;Weitzman & Fradet-Turcotte, 2018). Averting unfavourable outcomes of such host-virus interaction has been virusinduced optimisation of DDR-a noncanonical response with multiple layers of complexity.…”

“…This may ultimately result in abrogated genome replication and secondary burst of transcription. Luftig, 2014;Pancholi et al, 2017;Weitzman & Fradet-Turcotte, 2018). Noncanonical usurpation of DDR is how viruses ensure selective exploitation of certain DDR components while subverting others thereby mitigating untoward consequences.…”