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Discovery and characterization of the mobilization of linker and core histones during herpes simplex virus type 1 (HSV-1) infection Open Access


Other title
herpes simplex virus
Type of item
Degree grantor
University of Alberta
Author or creator
Conn, Kristen Lea
Supervisor and department
Schang, Luis (Biochemistry)
Examining committee member and department
Weller, Sandra (Molecular, Microbial and Structural Biology)
Barry, Michele (Medical Microbiology and Immunology)
Schultz, Michael (Biochemistry)
Hendzel, Michael (Experimental Oncology)
Department of Biochemistry

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Herpes simplex virus type 1 (HSV-1) genomes associate with histones in unstable nucleosomes during lytic infections. Nucleosome core particles are 146 base pairs of DNA wrapped around a histone octamer of two molecules of each H2A, H2B, H3, and H4. Histone H1 binds to nucleosomes at DNA entry and exit points. Association with histones is proposed to regulate HSV-1 gene expression. Consistently, HSV-1 transcription transactivators disrupt chromatin and HSV-1 strains mutant in these transactivators are replication impaired or transcriptionally inactive. HSV-1 genomes have dynamic associations with histones. The genomes are not associated with histones in capsids, and input genomes are delivered to nuclear domains depleted of histones. Later during infection, HSV-1 genomes again occupy nuclear domains depleted of histones. Histone synthesis is inhibited during infection and the total level of nuclear histones remains relatively constant. It is therefore unlikely that the histones that first bind to HSV-1 genomes are newly synthesized. The source of the histones that associate with HSV-1 genomes has yet to be addressed. Histones in cellular chromatin normally disassociate, diffuse through the nucleus, and re-associate at different sites. I propose that histones are mobilized from domains of cellular chromatin to those domains containing HSV-1 genomes in cellular attempts to silence HSV-1 gene expression. I additionally propose that HSV-1 further mobilizes histones to counteract such silencing attempts. My hypothesis is that histones are mobilized during HSV-1 infection. In this thesis, I show that linker and core histones are mobilized during HSV-1 infection. Such mobilization results in increases to their “free” (not bound to chromatin) pools. Linker and core histones were mobilized even when HSV-1 proteins were not expressed, mobilization that likely reflects cellular responses to infection. Histone mobilization was enhanced when HSV-1 IE or E proteins were expressed. This enhanced mobilization was independent of HSV-1 DNA replication and late proteins. Core histones H2B and H3.3 were differentially mobilized, suggesting that different mechanisms may mobilize histones during HSV-1 infection. My discovery of histone mobilization reveals a novel consequence of cell-virus interactions that addresses a previously unexplained aspect of HSV-1 infection.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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