The Ashkenazi-Centric G334R Variant of TP53 is Severely Impaired for Transactivation but Retains Tumor Suppressor...

Mutations in the TP53 tumor suppressor gene are the most abundant genetic occurrences in cancer. Some of these mutations lead to loss of function of p53 protein, some are gain of function, and some variants are hypomorphic (partially functional). Currently, there is no clinical distinction between different p53 mutations and cancer therapy or prognosis. Mutations in the oligomerization domain of p53 appear to be quite distinct in function, compared to mutations in the DNA binding domain. Here we show that, like other p53 oligomerization domain mutants, the Ashkenazi-specific G334R mutant accumulates to very high levels in cells and is significantly impaired for the transactivation of canonical p53 target genes. Surprisingly, we find that this mutant retains the ability to bind to consensus p53 target sites. A mouse model reveals that mice containing the G334R variant show increased predisposition to cancer, but only a fraction of these mice develop late-onset cancer. We show that the G334R variant retains the ability to interact with the SP1 transcription factor and contributes to the transactivation of joint SP1-p53 target genes. The combined evidence indicates that G334R is a unique oligomerization domain mutant that retains some tumor suppressor function.