Date of Completion


Embargo Period



HSV-1, DNA repair, recombination, antiviral, UL12, ICP0, DNA-PK, DNA

Major Advisor

Sandra K. Weller

Associate Advisor

Gordon Carmichael

Associate Advisor

Christopher Heinen

Associate Advisor

Bing Hao

Field of Study

Biomedical Science


Doctor of Philosophy

Open Access

Open Access


In order to promote lytic infection, HSV-1 manipulates components of the cellular DNA damage response (DDR). The central objective of this thesis was to determine whether UL12 and ICP0 act as mediators of DDR pathway choice in order to promote lytic infection. Classic non-homologous end joining (C-NHEJ) is antiviral, and we sought to determine whether an incoming viral genome alone was sufficient to activate C-NHEJ. We showed that infectivity of HSV-1 DNA could be restored by overexpression of ICP0 and in the cells deficient for DNA-PKcs. Thus, ICP0 may play an important role in promoting productive infection by inhibiting C-NHEJ. UL12-null (AN-1) produces wild-type levels of DNA, but growth is impaired. Thus, we asked whether AN-1 DNA was infectious, and determined that DNA produced by AN-1 was aberrant and non-infectious. We hypothesized that this was due to incorrect DDR pathway choice. To test this, we measured viral yields of UL12 mutant viruses on cells deficient for core C-NHEJ proteins and analyzed the DNA produced by pulsed-field gel electrophoresis. We found that AN-1 grows better and produces less aberrant DNA on C-NHEJ-deficient cells. To determine whether UL12 and ICP0 are sufficient to effect pathway choice, we used a plasmid-based repair reporter that measures the ratio of C-NHEJ activity to MMEJ activity. We showed that both ICP0 and UL12 inhibit aspects of the C-NHEJ pathway in order to promote productive infection. This work demonstrates that C-NHEJ is antiviral, and that correct DDR pathway choice is essential for productive HSV-1 infection.