Figure 8.

A model: E6 downregulates p53 function through HMT repression. (a) Previous reports indicate that, in HPV-non-infected cells, DNA-damage stress induces SET7-mediated p53 methylation and stabilization, as well as recruitment of p53 and its coactivators CARM1 and PRMT1 to p53-regulated genes for gene activation. (b) We demonstrate that, in HPV E6-expressing cells, in addition to directly targeting p53 for degradation through the E6AP pathway, E6 is able to inhibit SET7-mediated p53 methylation and thus reduce p53 protein stability. E6 can also target chromatin-bound p53 and repress the activities of the p53 coactivators CARM1 and PRMT1, leading to reduction of local histone methylation, which, likely, in turn dissociates p53 from chromatin. p53-dependent gene transcription is thus downregulated.