Genetic selection of intragenic suppressor mutations that reverse the effect of common p53 cancer mutations

Rainer K. Brachmann, Kexin Yu, Yolanda Eby, Nikola P. Pavletich, Jef D. Boeke

    Research output: Contribution to journalArticle

    Abstract

    Several lines of evidence suggest that the presence of the wild-type tumor suppressor gene p53 in human cancers correlates well with successful anti-cancer therapy. Restoration of wild-type p53 function to cancer cells that have lost it might therefore improve treatment outcomes. Using a systematic yeast genetic approach, we selected second-site suppressor 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 beneficial effects of these suppressor mutations were demonstrated using mammalian reporter gene and apoptosis assays. Further experiments showed that these suppressor mutations could override additional p53 cancer mutations. The mechanisms of such suppressor mutations can be elucidated by structural studies, ultimately leading to a framework for the discovery of small molecules able to stabilize p53 mutants.

    Original languageEnglish (US)
    Pages (from-to)1847-1859
    Number of pages13
    JournalEMBO Journal
    Volume17
    Issue number7
    DOIs
    StatePublished - Apr 1 1998

    Keywords

    • Human
    • Saccharomyces cerevisiae
    • Tumor suppressor
    • Yeast

    ASJC Scopus subject areas

    • Neuroscience(all)
    • Molecular Biology
    • Biochemistry, Genetics and Molecular Biology(all)
    • Immunology and Microbiology(all)

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