The p53 gene is mutated in most human cancers. Collectively, these alterations represent the most common genetic change shared across the spectrum of tumors seen in patients. p53 belongs to a class of "tumor suppressor" genes that restrict tissue growth, but we do not have a definitive molecular explanation for how this gene prevents cancers. To better understand actions of p53 that, when disabled, permit cancer formation we built sophisticated platforms in genetic model systems. Leveraging insights from these, we discovered that p53 normally restrains a class of mobile elements called retrotransposons. Unlike most genetic material, these otherwise silent elements can rapidly amplify and mo...

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The p53 gene is mutated in most human cancers. Collectively, these alterations represent the most common genetic change shared across the spectrum of tumors seen in patients. p53 belongs to a class of "tumor suppressor" genes that restrict tissue growth, but we do not have a definitive molecular explanation for how this gene prevents cancers. To better understand actions of p53 that, when disabled, permit cancer formation we built sophisticated platforms in genetic model systems. Leveraging insights from these, we discovered that p53 normally restrains a class of mobile elements called retrotransposons. Unlike most genetic material, these otherwise silent elements can rapidly amplify and move to new genomic positions, causing inflammation and unstable genomes. We have diverse lines of evidence and compelling clinical data suggesting that p53 loss permits eruptions of retrotransposons that could drive tumors. Research proposed here tests this hypothesis and defines the mechanism by which p53 normally silences these mobile elements in a cancer-prone platform. Since p53 lesions frequently arise in all cancer types, insights from this work should have broad impact and may enable new diagnostics or therapies that target retroelements.

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