P53 INHIBITS JC VIRUS-DNA REPLICATION IN-VIVO AND INTERACTS WITH JC VIRUS LARGE T-ANTIGEN

The onset of DNA replication is an important step within the life cycl e of the human neurotropic polyomavirus JC. In this report, evidence t hat both the human and the murine tumor suppressor protein p53 strongl y inhibit JCV DNA replication in vivo is presented. This inhibition is dose-dependent and not a secondary effect of a decreased expression o f JCV large T-antigen in response to p53. Using deletion mutants of mu rine 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, del etion of the highly conserved central region of p53 abolished the inhi bitory effect on replication. The tumor-derived human mutant p53(His27 3) inhibited JCV DNA replication significantly, whereas another tumori genic 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 r esults strongly suggest that p53 inhibits JCV DNA replication by inter acting with JCV large T-antigen. (C) 1996 Academic Press, Inc.