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Theses Doctoral

Host factors regulating retroviral replication by interactions with viral RNA and DNA

Wang, Gary Zhe

Retroviruses are capable of infecting diverse vertebrates, and successful infection requires intimate interaction between virus and the host cell. During an infection, retroviral particles must bind specifically to cell surface receptors on the target cell, cross the plasma membrane, reverse-transcribe their RNA genome into double stranded DNA, find their way to the nucleus, enter the nucleus and integrate its DNA into host chromosomes. Following integration, expression of viral mRNA ensues, followed by viral mRNA export into the cytoplasm, translation of viral mRNA into proteins, and assembly of new virions that will egress from the host cell. We now appreciate that at many steps of this complex process, the virus must hijack the cellular machinery to replicate. At the same time, the host cell mobilizes a variety of cellular defense mechanisms to suppress viral infection. This thesis investigates various aspects of virus-host interactions. I will first describe the involvement of cellular transcriptional repressor protein ErbB3 binding protein 1 (EBP1) in facilitating transcriptional shutdown of Moloney murine leukemia virus (MLV) gene expression in mouse embryonic cells. Next, I describe a novel means of regulating the activity of Yin Yang 1 (YY1), a cellular transcription factor regulating retroviral gene expression, through post-translational modifications. I show that YY1 is a target of tyrosine phosphorylation by Src family kinases. Phosphorylation of YY1 impairs its ability to bind DNA and RNA, thereby downregulating its activity as a transcription factor on retroviral and cellular promoters. Apart from studying retroviral gene expression, I have also investigated intrinsic cellular defenses against retroviral infection. This is exemplified by our finding that mouse cells are intrinsically resistant to infection by betaretroviruses such as Mason-Pfizer monkey virus (M-PMV). The block against M-PMV occurs after reverse transcription and prior to viral nuclear entry. Finally, I will present ongoing work examining the fate of viral DNAs following infection, focusing on the kinetics of its association with cellular core histones and viral structural proteins. Together, this work provides critical insights into numerous aspects of the virus-host interactions.

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More About This Work

Academic Units
Cellular, Molecular and Biomedical Studies
Thesis Advisors
Goff, Stephen P.
Degree
Ph.D., Columbia University
Published Here
April 6, 2016
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