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The mechanism of inhibition of herpes simplex virus type 1 DNA replication by roscovitine

Transcription and DNA replication of herpes simplex virus type 1 (HSV-1) occur in nuclear domains adjacent to structures named ND10. The HSV-1 single-stranded DNA binding protein ICP8 localizes to these nuclear domains to direct the assembly of the pre- and replication compartments.
Inhibition of cyclin dependent kinases with roscovitine inhibits HSV-1 DNA replication, even in the presence of all required HSV-1 proteins, at an unidentified step. Here I show that roscovitine inhibits the localization of pre-expressed ICP8 to new replication sites. Therefore, the inhibition of HSV-1 DNA replication occurs at a step prior to initiation. I next evaluated the mechanisms of inhibition of proper ICP8 localization. ICP8 was extracted at lower salt concentrations from roscovitine-treated than untreated cells, but the affinity of ICP8 for ssDNA in vitro was not affected.
I propose that roscovitine inhibits HSV-1 DNA replication by inhibiting DNA accessibility. I also discuss alternative mechanisms.

Identiferoai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:AEU.10048/1820
Date06 1900
CreatorsNewman, Emma
ContributorsSchang, Luis (Biochemistry and Medical Microbiology and Immunology), Goping, Ing Swie (Biochemistry), Schultz, Mike (Biochemistry), Wang, Zhixiang (Cell Biology)
Source SetsLibrary and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada
Languageen_US
Detected LanguageEnglish
TypeThesis
Format7533742 bytes, application/pdf

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