Human cytomegalovirus exploits host chromatin remodeler MORC2 to promote the DNA damage response on viral genomes.

Human cytomegalovirus (HCMV) harbors a 230-kb double-stranded DNA genome whose replication induces extensive DNA damage during lytic infection. Because HCMV lacks canonical DNA repair machinery, it relies on host DNA damage response (DDR) pathways. However, the mechanisms that govern the preferential recruitment and function of host DDR proteins on viral genomes remain poorly understood. Here, we show that HCMV co-opts the host chromatin remodeler MORC Family CW-type zinc finger 2 (MORC2) to promote DDR activation on viral genomes. HCMV infection induces MORC2 expression, which is important for efficient viral DNA replication and progeny virus production. We found that MORC2 redistributes to viral replication compartments (vRCs) in HCMV-infected cells and enhances viral chromatin accessibility in an ATPase-dependent manner, thereby facilitating γH2AX accumulation and the recruitment of DNA repair factors to vRCs. Furthermore, we found that HCMV UL112-113-mediated phase separation facilitates MORC2 recruitment to vRCs, promoting efficient DDR signaling on viral genomes. Together, these findings provide a mechanistic framework for how DNA viruses alleviate replication stress by hijacking host chromatin remodelers.