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Published on: July 23, 2010
p53 inhibits JC virus DNA replication in vivo and interacts with JC virus large T-antigen
Abstract:
The onset of DNA replication is an important step within the life cycle of the human neurotropic polyomavirus JC. In this report, evidence that both the human and the murine tumor suppressor protein p53 strongly inhibit JCV DNA replication in vivo is presented. This inhibition is dose-dependent and not a secondary effect of a decreased expression of JCV large T-antigen in response to p53. Using deletion mutants of murine p53 and tumor-derived point mutations of human p53, the basis of the suppression of JCV DNA replication by p53 was dissected. Deletion of either the amino- or the carboxy-terminal domain of murine p53 did not interfere with the repression of JCV DNA replication. However, deletion of the highly conserved central region of p53 abolished the inhibitory effect on replication. The tumor-derived human mutant p53(His273) inhibited JCV DNA replication significantly, whereas another tumorigenic mutant, p53(His175), had no inhibitory effect Concomitantly, a direct protein-protein interaction between p53 and JCV large T-antigen was lost in mutants which did not affect JCV DNA replication. These results strongly suggest that p53 inhibits JCV DNA replication by interacting with JCV large T-antigen.
Insights
The tumor suppressor protein p53 inhibits human neurotropic polyomavirus JC (JCV) DNA replication. This inhibition occurs through direct interaction between p53 and the JCV large T-antigen.
Area of Science:
- Virology
- Molecular Biology
- Oncology
Background:
- DNA replication is crucial for the JC polyomavirus (JCV) life cycle.
- The tumor suppressor protein p53 plays a role in regulating cellular processes.
Purpose of the Study:
- To investigate the effect of human and murine p53 on JCV DNA replication.
- To determine the mechanism by which p53 inhibits JCV DNA replication.
Main Methods:
- In vivo studies using deletion mutants of murine p53 and human p53 point mutants.
- Analysis of JCV large T-antigen expression and protein-protein interactions.
Main Results:
- Both human and murine p53 dose-dependently inhibited JCV DNA replication.
- The inhibitory effect of p53 required its central conserved region.
- p53 mutants that failed to inhibit replication also lost direct interaction with JCV large T-antigen.
Conclusions:
- p53 directly inhibits JCV DNA replication.
- The interaction between p53 and JCV large T-antigen is essential for this inhibition.
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