Viral Modulation of the DNA Damage Response and Innate Immunity: Two Sides of the Same Coin

[Display omitted] •Modulating the DDR is integral to viral replication and evolutionarily conserved by diverse viruses.•The DDR can be both beneficial and antiviral.•Engagement of the DDR by viruses cause cellular consequences that are interconnected.•There is extensive crosstalk between the DDR and innate immunity.•The lack of DDR-specific experiments and assays has hindered the ability to move the field forward. The DDR consists of multiple pathways that sense, signal, and respond to anomalous DNA. To promote efficient replication, viruses have evolved to engage and even modulate the DDR. In this review, we will discuss a select set of diverse viruses and the range of mechanisms they evolved to interact with the DDR and some of the subsequent cellular consequences. There is a dichotomy in that the DDR can be both beneficial for viruses yet antiviral. We will also review the connection between the DDR and innate immunity. Previously believed to be disparate cellular functions, more recent research is emerging that links these processes. Furthermore, we will discuss some discrepancies in the literature that we propose can be remedied by utilizing more consistent DDR-focused assays. By doing so, we hope to obtain a much clearer understanding of how broadly these mechanisms and phenotypes are conserved among all viruses. This is crucial for human health since understanding how viruses manipulate the DDR presents an important and tractable target for antiviral therapies.