DNA viruses and the cellular DNA-damage response

Abstract

It is clear that a number of host-cell factors facilitate virus replication and, conversely, a number of other factors possess inherent antiviral activity. Research, particularly over the last decade or so, has revealed that there is a complex inter-relationship between viral infection and the host-cell DNA-damage response and repair pathways. There is now a realization that viruses can selectively activate and/or repress specific components of these host-cell pathways in a temporally coordinated manner, in order to promote virus replication. Thus, some viruses, such as simian virus 40, require active DNA-repair pathways for optimal virus replication, whereas others, such as adenovirus, go to considerable lengths to inactivate some pathways. Although there is ever-increasing molecular insight into how viruses interact with host-cell damage pathways, the precise molecular roles of these pathways in virus life cycles is not well understood. The object of this review is to consider how DNA viruses have evolved to manage the function of three principal DNA damage-response pathways controlled by the three phosphoinositide 3-kinase (PI3K)-related protein kinases ATM, ATR and DNA-PK and to explore further how virus interactions with these pathways promote virus replication. IntroductionThe DNA-damage response (DDR) is a general term employed to describe a complex series of cellular pathways that detect DNA damage, initiate cell-cycle arrest so that mutated DNA is not duplicated, and then go on to repair the lesion or, if damage is too great, trigger apoptosis. Infection by many virus species is sufficient to initiate a DDR, activating some or all of the repair pathways. Simplistically, this has been seen as recognition by the host cell of viral DNA as its own damaged DNA, but it is now considered that this could, at least to some extent, be an antiviral response, aimed directly at combating infection. Viruses have a complex series of mechanisms that, in turn, have evolved to combat and inactivate the cellular damage-response pathways.The aim of this review is to consider how and why different viruses affect the balance of these opposing pathways: for example, to what extent is an activated DDR directly required by particular virus species to facilitate or assist virus replication or, conversely, to what extent does the cellular damage response hinder replication. Additionally, it is often not clear whether activation of the DDR is a mere byproduct of infection or a direct result of 'intentional' action of viral protein activity. If DDR activation is an unwanted result of infection, a further point of interest is to understand what measures viruses take to circumvent the deleterious effects of the cellular pathways. Past experience would suggest that viruses are so highly evolved and their primary structures so tightly constrained that the selective activation of DDR pathways by some viruses might prove advantageous to them. Whether this is the case will only become evident after considerable further investigation.The r...

Baculovirus F-Box Protein LEF-7 Modifies the Host DNA Damage Response To Enhance Virus Multiplication

“…It is well established that diverse viruses, including the human herpesviruses, papillomaviruses, HIV, and adenoviruses, activate the host DDR and in the process trigger ␥-H2AX accumulation (1,8,12). The DNA baculoviruses also engage the host DDR as a means to facilitate vDNA replication and stimulate multiplication (2,3).…”

“…Nonetheless, certain DNA viruses, such as the mammalian herpesviruses and insect baculoviruses, require the host DDR for efficient multiplication (2)(3)(4)(5)(6)(7). Therefore, these viruses frequently activate the DDR but alter this response to ablate its antiviral effects and exploit its proviral functions (1,8). To this end, DNA viruses encode factors that modify or degrade key DDR components.…”

Human Papillomavirus Episome Stability Is Reduced by Aphidicolin and Controlled by DNA Damage Response Pathways

“…DNA viruses have a close association with DNA damage response (DDR) pathways, which are increasingly recognized as a first line of cellular antiviral defense (27,28). Viruses represent a threat to genomic stability, and as such, the host cell acts to minimize genome damage and eliminate the foreign DNA.…”

Kaposi's Sarcoma-Associated Herpesvirus MicroRNAs Target GADD45B To Protect Infected Cells from Cell Cycle Arrest and Apoptosis

“…There exists a complicated relationship between DNA viruses and host DNA damage responses (9,(33)(34)(35)(36). Some responses can trigger an antiviral response, while other interactions between the cellular DNA damage response factors can promote viral replication.…”