Human T-Cell Leukemia Virus Type I Basic Leucine Zipper Factor (HBZ) Modulates Cellular DNA Damage Repair and Antioxidant Responses to Promote Host Cell Survival and Leukemogenesis

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)
Amanda Williams Rushing (Creator)
Institution
East Carolina University (ECU )
Web Site: http://www.ecu.edu/lib/

Abstract: Approximately twenty million people worldwide are infected with Human T-cell Leukemia Virus type 1 (HTLV-1). HTLV-1 establishes a life-long , chronic infection which can result in the development of severe HTLV-1 associated diseases: Adult T-cell Leukemia (ATL) or HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP). ATL is a fatally-aggressive lymphoproliferative disorder of HTLV-1-infected CD4+ T-cells. HAM/TSP is a debilitating neurodegenerative disorder that greatly reduces quality of life. There exists a distinct lack of effective vaccine and therapeutic options for both ATL and HAM/TSP patients. Though the mechanisms that drive HTLV-1 pathogenesis remain poorly understood , extensive study of the virus has revealed the importance of two viral regulatory proteins in disease progression: Tax and HBZ. Tax is a transcriptional regulator which is important for establishing initial infection; however , Tax is highly immunogenic and stimulates a robust antiviral immune response. To evade immune detection , HTLV-1 host cells often silence Tax expression through the transcriptionally repressive activity of the basic leucine zipper factor HBZ. HBZ is expressed throughout all phases of infection and plays important roles in maintaining host cell survival and clonal expansion. HBZ expression is sufficient to induce ATL-like disease progression in in vivo models , supporting its contribution to leukemogenesis in patients. Here , we report novel functions of HBZ that may promote the long-term survival of infected lymphocytes , including the direct upregulation of antioxidant response gene expression , the detoxification of reactive oxygen species , and the prevention of oxidative stress-induced cell death. We also evaluated the contribution of HBZ to the accumulation of genetic abnormalities which may promote leukemogenesis. Here , we report that HBZ contributes to genetic instability by affecting the double-stranded DNA damage repair system non-homologous end joining (NHEJ) , possibly through specific interactions with DNA repair proteins. These findings support the role of HBZ in promoting leukemogenesis through the accumulation of chromosomal abnormalities which arise from double-stranded DNA breaks. Together , the data presented here indicate that HBZ is an important driving force in the prolonged survival and transformation of HTLV-1-infected lymphocytes.

Additional Information

Publication
Dissertation
Language: English
Date: 2018
Keywords
HBZ, leukemogenesis, NHEJ, Ku70, Ku80, DNA-PK, HMOX-1, small Maf, antioxidant, oxidative stress
Subjects

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TitleLocation & LinkType of Relationship
Human T-Cell Leukemia Virus Type I Basic Leucine Zipper Factor (HBZ) Modulates Cellular DNA Damage Repair and Antioxidant Responses to Promote Host Cell Survival and Leukemogenesishttp://hdl.handle.net/10342/6782The described resource references, cites, or otherwise points to the related resource.