Unlike RNA viruses, which typically encode their own RNA-dependent RNA polymerases, DNA viruses typically utilize host RNA Polymerase II (RNAPII) to transcribe their genes. Therefore, host factors that interact with RNAPII often maintain important regulatory roles during DNA virus infections. Senataxin (SETX) is a ubiquitously expressed 303 kDa RNA:DNA helicase that associates with RNAPII. It is involved in the resolution of R-loops and plays a role during the DNA damage response. Mutations in SETX are implicated in the neurodegenerative diseases Type 2 Ataxia with Oculomotor Apraxia (AOA2) and juvenile Amyotrophic Lateral Sclerosis (ALS4). Recent work from our group has demonstrated that SETX also acts as an antagonist of the antiviral response during RNA virus infections. Infections, including those caused by Herpes Simplex Virus type I (HSV-1), have been identified as potential environmental triggers of neurodegenerative diseases. Therefore, we elected to study the role of SETX during DNA virus infections since, in addition to regulating host genes, it may also play a role in viral transcription and/or DNA replication. Our data suggests that SETX is involved in the regulation of viral gene expression, and that SETX facilitates DNA replication and contributes to viral biogenesis. SETX attenuates the antiviral response, and in mouse models of infection, is protective against HSV-1 disease pathogenesis. These studies have enhanced our understanding of the role played by SETX during viral infection and may shed light on the mechanism(s) through which SETX dysfunction results in neurodegenerative diseases. / Thesis / Master of Health Sciences (MSc) / DNA viruses utilize host proteins in gene expression, therefore, associated factors play roles during DNA virus infections. Senataxin (SETX) is a RNA:DNA helicase associated with these proteins. SETX mutations are implicated in the neurodegenerative diseases Type 2 Ataxia with Oculomotor Apraxia (AOA2) and juvenile Amyotrophic Lateral Sclerosis (ALS4). Recently, our group demonstrated SETX antagonizes antiviral responses to RNA virus infections. Infections, including those caused by Herpes Simplex Virus type I (HSV-1), are identified as potential triggers of neurodegenerative diseases. We elected to study the role of SETX during DNA virus infections. Our data suggests that SETX is involved in the regulation of viral gene expression, facilitates HSV-1 DNA replication, attenuates the antiviral response, and in mouse models of infection, is protective against HSV-1 disease pathogenesis. These studies enhance understanding of the role of SETX during viral infection and may shed light on the mechanism(s) of SETX role in neurodegenerative disease.