Date of Award

Spring 5-2026

Document Type

Thesis (Master's)

Department or Program

Molecular and Systems Biology

First Advisor

Giovanni Bosco

Second Advisor

Felicia Goodrum

Third Advisor

David Leib

Abstract

Human cytomegalovirus (HCMV) is a large double stranded DNA virus and member of the Herpesviridae family. Like all herpesviruses, HCMV presents with characteristics of persistent, lifelong infections that transition between lytic and latent states. The replication of the viral genome is traditionally thought to occur by a rolling circle mechanism, but this model is supported by little evidence. It is known that HCMV actively recruits several host proteins to viral replication compartments (RCs), including proteins involved in the DNA damage response (DDR). The exact mechanisms of how these proteins are used and in what ways they help the virus remain poorly understood. To begin to understand how host DNA repair and replication proteins are involved in viral genome synthesis, we first examined human polymerase delta (δ), a main replicative polymerase in eukaryotic semi-conservative DNA synthesis, as well as the major polymerase for eukaryotic repair mechanisms. We found polymerase δ is excluded from viral RCs and does not contribute to viral genome synthesis, despite being a major contributor to repair mechanisms. Interestingly, the additional accessory subunits of polymerase δ also do not directly contribute to viral genome synthesis, despite POLD3 being a shared subunit of the translesion polymerase ζ, which has been shown to be important for viral DNA replication. Together, these results help shape our understanding as to how host proteins contribute to the fidelity of HCMV and the mechanisms of DNA synthesis to provide better antiviral solutions in the future.

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