DNA Damage Response Mechanisms in Viral Infections

Viruses that deliver or generate DNA within host cells routinely engage the cellular DNA damage response (DDR), a finely tuned network of sensors, transducers and effectors evolved to detect and repair lesions and maintain genomic integrity. Upon infection, DNA viruses such as herpesviruses, papillomaviruses and parvoviruses provoke activation of key kinases—including ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR)—that phosphorylate downstream factors to orchestrate cell-cycle checkpoints, DNA repair pathways and, in some cases, apoptosis. Many viruses have developed countermeasures to subvert or exploit these pathways: some express proteins that inhibit DNA-damage sensors or redirect repair complexes to support viral replication, while others harness DDR-induced cell-cycle arrest to optimise resources for genome synthesis. Beyond DNA viruses, an emerging body of evidence indicates that RNA viruses can indirectly instigate DNA lesions and manipulate DDR signalling to favour replication or modulate host defence. The interplay between virus and host DDR is bidirectional: while DDR activation may restrict early stages of infection, strategic viral manipulation of repair machinery can enhance genome stability of the viral nucleic acid and, in some instances, contribute to oncogenic transformation. Understanding these molecular dialogues reveals new angles for antiviral development, oncolytic virotherapy and the mitigation of virus-associated malignancies.

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DNA Damage Response Mechanisms in Viral Infections publication trend

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Technical terms

ATM kinase: A serine/threonine protein kinase activated by DNA double-strand breaks that phosphorylates multiple substrates to coordinate cell-cycle checkpoint arrest and repair.

ATR kinase: A related kinase chiefly responsive to replication stress and single-stranded DNA, promoting stabilisation of stalled forks and checkpoint control.

MRN complex: A trimeric sensor composed of MRE11, RAD50 and NBS1 that recognises DNA ends, recruits ATM and initiates double-strand break repair.

Replication stress: A cellular state in which DNA synthesis is impeded, leading to stalled forks, single-strand DNA accumulation and activation of ATR-mediated signalling.

Homology-directed repair: An accurate pathway for double-strand break repair that uses an undamaged DNA template to restore sequence fidelity, often suppressed by viruses to avoid cellular control.

References

1. For better or worse: crosstalk of parvovirus and host DNA damage response. Frontiers in Immunology (2024).
2. The immediate-early protein 1 of human herpesvirus 6B interacts with NBS1 and inhibits ATM signaling. EMBO Reports (2024).
3. Genomes of the autonomous parvovirus minute virus of mice induce replication stress through RPA exhaustion. PLOS Pathogens (2023).
4. Activation of the DNA Damage Response by RNA Viruses. Biomolecules (2016).