GENETIC SELECTION OF INTRAGENIC SUPPRESSOR MUTATIONS THAT REVERSE THEEFFECT OF COMMON P53 CANCER MUTATIONS

Several lines of evidence suggest that the presence of the wild-type t umor suppressor gene p53 in human cancers correlates well with success ful anti-cancer therapy. Restoration of wild-type p53 function to canc er cells that have lost it might therefore improve treatment outcomes. Using a systematic yeast genetic approach, we selected second-site su ppressor mutations that can overcome the deleterious effects of common p53 cancer mutations in human cells. We identified several suppressor mutations for the V143A, G245S and R249S cancer mutations. The benefi cial effects of these suppressor mutations were demonstrated using mam malian reporter gene and apoptosis assays. Further experiments showed that these suppressor mutations could override additional p53 cancer m utations. The mechanisms of such suppressor mutations can be elucidate d by structural studies, ultimately leading to a framework for the dis covery of small molecules able to stabilize p53 mutants.