Dominant-Negative p53 Mutations Selected in Yeast Hit Cancer Hot Spots

• Published in: Proceedings of the National Academy of Sciences - PNAS 1996-04, Vol.93 (9), p.4091-4095
• Main Authors: Brachmann, Rainer K., Vidal, Marc, Boeke, Jef D.
• Format: Article
• Language: English
• Subjects: Alleles; Amino Acid Sequence; Base Sequence; Binding sites; Blotting, Western; Cancer; Cloning, Molecular; Codon; Codons; DNA; Genes, Dominant; Genes, p53; Genetic mutation; Genetics; Genotype; Humans; Molecular Sequence Data; Mutation; Neoplasms - genetics; Phenotype; Phenotypes; Plasmids; Point Mutation; Proteins; Saccharomyces cerevisiae - genetics; Tumor Suppressor Protein p53 - biosynthesis; Tumor Suppressor Protein p53 - isolation & purification; Yeast; Yeasts
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.9.4091

Clinically important mutant p53 proteins may be tumorigenic through a dominant-negative mechanism or due to a gain-of-function. Examples for both hypotheses have been described; however, it remains unclear to what extent they apply to TP53 mutations in general. Here it is shown that the mutational spectrum of dominant-negative p53 mutants selected in a novel yeast assay correlates tightly with p53 mutations in cancer. Two classes of dominant-negative mutations are described; the more dominant one affects codons that are essential for the stabilization of the DNA-binding surface of the p53 core domain and for the direct interaction of p53 with its DNA binding sites. These results predict that the vast majority of TP53 mutations leading to cancer do so in a dominant-negative fashion.