Impairment of DNA repair by oncogenic virus HHV8

Abstract

Cancer is a growing disease burden worldwide. Lifestyle and environmental factors are the largest contributors to cancer development (90-95%) in contrast to genetics (5-10% of cases,); of the environmental factors, infections contribute 15-20% of the "external" risk in developing cancer. In the US, breast cancer is the most common type of cancer with 284,000 new cases expected in 2021, with the next most common being prostate and lung cancer. Viruses have long been suspected to promote cancerous transformations. Kaposi Sarcoma Associated Herpesvirus (KSHV) is implicated in Kaposi Sarcoma (KS) cancer transformation and in vitro is found in BCBL1 cells. KSHV is a herpesvirus, also named Human Herpesvirus 8 (HHV8). The connection between viral infection and increase in cancer has been documented, but the details of cellular mechanisms involved therein are lacking. We hypothesize that during active viral infection, cellular DNA is not repaired properly, leading to the accumulation of DNA damage and mutations; these in turn, could lead to the transformation of normal, albeit virus-infected cells, into cancer-predisposed cells, and later tumor formation. The goal of this thesis was to investigate DNA repair during an active viral infection of HHV8. BCBL1 is a clonal lymphoma cell line isolated in 1995 from an HIV seronegative patient with a body cavity-based lymphoma. Chapter 1 is a mini review on what is known about this oncogenic virus, DNA repair pathways, and cancer and how these three relate to each other is discussed. Chapter 2 compares DNA repair dynamics of two distinct repair pathways in virally active cells versus virally dormant cells. Our research suggests that host processes controlling DNA repair mechanisms are manipulated to favor virus production. Chapter 3 is a general conclusion summarizing our significant findings from Chapter 2.