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DNA Damage Response Suppresses Epstein-Barr Virus-Driven Proliferation of Primary Human B Cells

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Date
2012
Author
Nikitin, Pavel A.
Advisor
Luftig, Micah A
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Abstract

The interaction of human tumor viruses with host growth suppressive pathways is a fine balance between controlled latent infection and virus-induced oncogenesis. This dissertation elucidates how Epstein-Barr virus interacts with the host growth suppressive DNA damage response signaling pathways (DDR) in order to transform infected human B lymphocytes.

Here I report that the activation of the ATM/Chk2 branch of the DDR in hyper-proliferating infected B cells results in G1/S cell cycle arrest and limits viral-mediated transformation. Similar growth arrest was found in mitogen-driven proliferating of B cells that sets the DDR as a default growth suppressive mechanism in human B cells. Hence, the viral protein EBNA3C functions to attenuate the host DDR and to promote immortalization of a small portion of infected B cells. Additionally, the pharmacological inhibition of the DDR in vitro increases viral immortalization of memory B cells that facilitates the isolation of broadly neutralizing antibodies to various infectious agents. Overall, this work defines early EBV-infected hyper-proliferating B cells as a new stage in viral infection that determines subsequent viral-mediated tumorigenesis.

Type
Dissertation
Department
Molecular Genetics and Microbiology
Subject
Virology
Genetics
Oncology
B cell
Chk2
DNA damage response
EBNA-3C
Epstein-Barr virus
monoclonal antibody
Permalink
https://hdl.handle.net/10161/6183
Citation
Nikitin, Pavel A. (2012). DNA Damage Response Suppresses Epstein-Barr Virus-Driven Proliferation of Primary Human B Cells. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/6183.
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States License.

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