Antiviral role of Condensin II

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PROJECT SUMMARY – LONGWORTH, MICHELLE S./ O’CONNOR, CHRISTINE M. Invading pathogens, such as viruses and bacteria, rapidly alter cellular homeostasis. Cellular homeostasis is maintained by both epigenetics and higher order chromatin organization, and the condensin II complex plays essential roles in regulating these processes. However, our understanding of condensin II’s contribution to host cell DNA organization during infection is minimal. Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus, prevalent in >70% of the US population. Immune compromised individuals are at heightened risk for complications from HCMV infection, for which there is currently no cure or vaccine. Thus, there is a clear, unmet need for development of novel therapeutic strategies, necessitating a better understanding of the host-pathogen relationship. Our preliminary data show that HCMV infection upregulates the condensin II protein NCAPD3, and that NCAPD3 restricts viral replication, although the underlying mechanisms remain unknown. The overall objective of this proposal is to determine the impact of HCMV infection on NCAPD3/condensin II-mediated chromatin organization and gene transcription. Our central hypothesis is that NCAPD3/condensin II restricts HCMV lytic replication through its ability to regulate chromatin accessibility. We propose to test this hypothesis through the following aims: AIM1. Determine the effects of NCAPD3 expression on HCMV lytic infection. AIM2. Identify NCAPD3-mediated changes to gene expression and chromatin accessibility in response to HCMV infection. The expected outcomes of our proposal include defining how CAP-D3 combats HCMV infection through chromosomal regulation, while revealing the means by which this novel antiviral factor is regulated during infection. Impact: Results will provide a comprehensive understanding of host cell dynamics in response to viral infection and lay the foundation for future development of novel therapeutics to combat HCMV infection and disease.