DNA damage responses in HCMV infection: emerging mechanisms and outstanding questions

The cellular DNA damage response (DDR) is essential for maintaining genome integrity in the face of exogenous assault, as well as errors and breaks introduced during DNA replication. The DDR is a complex network of cellular processes that detects the type and severity of DNA damage and coordinates downstream actions. These include activating specific DNA repair pathways, including cell cycle arrest to allow time for repair, and-if the damage is irreparable-triggering apoptosis to eliminate cells with compromised genomes. DNA viruses have evolved multiple strategies to evade, suppress, or even hijack host DDR factors to promote their own replication. In the absence of such countermeasures, the activation of the host DDR may rapidly detect viral genomes as aberrant DNA, and restrict viral infection. Paradoxically, many DNA viruses depend on many aspects of the host DDR to ensure efficient replication of their genomes. Here, we focus on human cytomegalovirus (HCMV), a beta-herpesvirus with a large complex double-stranded DNA genome, and its relationship with host DDR. Although HCMV infects most of the human population, fundamental gaps remain in understanding how viral replication modulates a robust cellular DDR or recruits it for its own replication. Moreover, the roles of DDR in restricting viral DNA (vDNA) replication, promoting entry into latency, stabilizing latent genomes during cellular proliferation, and promoting vDNA synthesis following infection or reactivation from latency remain poorly understood.