The DNA damage response occurs in response to breaks in DNA and can elicit cell signaling pathways that result in cell cycle arrest, DNA repair, or apoptosis in order to maintain the integrity of the genome. The replication of viruses activates the host DNA damage response and many of these viruses have evolved mechanisms to inhibit apoptosis. To understand better the link between DNA damage and cellular defense, the effects of agents that create double-stranded DNA breaks were evaluated on cellular gene expression. Etoposide, a chemotherapeutic drug used to treat various cancers, causes cell cycle arrest and death by apoptosis. Its mechanism of action involves the targeting of topoisomerase II, wherein it alters the ability of topoisomerase II to relegate cleaved DNA strands, resulting in an increase the number of double stranded breaks in the DNA. This damage triggers cell death pathways, ultimately leading to apoptosis. The gene expression profile of etoposide treated cells was compared to that of virally infected cells.These studies indicate that etoposide treatment leads to expression of interferon (IFN) stimulated genes (ISGs). Further analysis indicated that a subset of IFNΑ and IFNΛ genes, but not IFNΒ, are induced by the DNA damage incurred with etoposide treatment and the ISGs are expressed due to IFN signaling. The IFN Regulatory Factors (IRFs), IRF3 and IRF5 do not appear to be activated and thus are not responsible for this IFN gene induction. However, two other IRF family members, IRF1 and IRF7 are induced in response to etoposide treatment and have a role in IFNΑ and IFNΛ induction. Furthermore, NFΚB appears to be the master transcription factor that activates IFN signaling in response to etoposide. In addition to directly activating IFNΛ gene expression, NFΚB also induces the IRF1 and IRF7 genes and therefore plays an indirect role in IFNΑ induction.Additionally, inhibition of PI-3-kinase ataxia-telangiectasia mutated (ATM) activation diminishes the IFNΑ and IFNΛ<em>f</em>nresponse in etoposide treated cells, indicating that the IFN induction appears to occur downstream of the (ATM) signaling pathway. These studies indicate a significant link between two host survival mechanisms. the DNA damage response and the response to viral infection.