Human cells encode up to 15 DNA polymerases with specialized functions in chromosomal DNA synthesis and damage repair. By contrast, complex DNA viruses, such as those of the herpesviridae family, encode a single high-fidelity DNA polymerase. This disparity raises the possibility that DNA viruses may rely on host polymerases for synthesis through complex DNA geometries. We tested the importance of error-prone Y-family polymerases involved in translesion synthesis (TLS) to human cytomegalovirus (HCMV) infection. We find most Y-family polymerases involved in the nucleotide insertion and bypass of lesions restrict HCMV genome synthesis and replication. By contrast, other TLS polymerases, such as the polymerase zeta complex, which extends past lesions, was required for optimal genome synthesis and replication. Depletion of either the polymerase zeta complex or the suite of insertion polymerases demonstrate that TLS polymerases suppress the frequency of viral genome rearrangements, particularly at GC-rich sites and repeat sequences. Moreover, while distinct from HCMV, replication of the related herpes simplex virus type 1 (HSV-1) is impacted by host TLS polymerases, suggesting a broader requirement for host polymerases for DNA virus replication. These findings reveal an unexpected role for host DNA polymerases in ensuring viral genome stability.
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