γ-Herpesvirus Kinase Actively Initiates a DNA Damage Response by Inducing Phosphorylation of H2AX to Foster Viral Replication

DNA virus infection can elicit the DNA damage response in host cells, including ATM kinase activation and H2AX phosphorylation. This is considered to be the host cell response to replicating viral DNA. In contrast, we show that during infection of macrophages murine γ-herpesvirus 68 (γHV68) actively induces H2AX phosphorylation by expressing a viral kinase (orf36). γHV68-encoded orf36 kinase and its EBV homolog, BGLF4, induce H2AX phosphorylation independently of other viral genes. The process requires the kinase domain of Orf36 and is enhanced by ATM. Orf36 is important for γHV68 replication in infected animals, and orf36, H2AX, and ATM are all critical for efficient γHV68 replication in primary macrophages. Thus, activation of proximal components of the DNA damage signaling response is an active viral kinase-driven strategy required for efficient γ-herpesvirus replication.