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Activity of tumor-antigens in polyomavirus replication
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Polyomavirus replication needs an active cell environment, and the viral DNA replication is cell cycle regulated. Tumor antigens (T-antigens) of mouse polyomavirus, especially large T-antigen, are necessary for the replication. Large T- antigen is a multifunctional protein, and like other T-antigens, its N-terminal region functions as a DnaJ-domain. This thesis focuses on identification of the factors regulating polyomavirus DNA replication.

Large T-antigen is a phosphoprotein which is the only essential viral protein in the initiation viral DNA replication. We found that the host cell cycle is critical for viral DNA replication and that threonine 278 of large T-antigen is a G2/M phase cyclin- dependent kinase phosphorylation site, regulating viral DNA replication.

In the DnaJ-domain, the first alpha-helix is important for T-antigen function, especially for its ability to regulate viral DNA replication. Mutant L13V large T- antigen is defective in the regulation of DNA replication, whereas the trans-activating function of mutant large T-antigens does not change. When all results are considered, we conclude that the functional defect of L13V large T-antigen is not related to the known activity of J-domain, it is possibly due to underphosphorylation of the mutant protein.

One of the biochemical properties of large T-antigen is DNA binding. A mutant large T-antigen (D286N) in which the mutated site is close to the DNA-binding domain was able to rescue viral DNA replication of a mutant with a base substitution in the origin of replication (G4A). BIAcore analysis showed no significant difference in the interaction between the mutant and wild-type large T-antigens with that could explain their different activities in vivo. However, in a cotransfection experiment we found that the D286N mutant large T-antigen showed strongly increased activity in the initiation of DNA replication at both the wild-type and mutant origin of replication.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2001. , 49 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 985
Keyword [en]
Biochemistry, Tumor-Antigens, DNA Replication, Cell-cycle, Phosphorylation, J-domain
Keyword [sv]
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Medical Virology
URN: urn:nbn:se:uu:diva-569ISBN: 91-554-4904-2OAI: oai:DiVA.org:uu-569DiVA: diva2:166064
Public defence
2001-01-23, lecture hall C8-305, BMC, Uppsala, 09:15
Available from: 2001-01-02 Created: 2001-01-02Bibliographically approved

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