Thursday, April 25, 2024
4/25/2024
Summary The p53 gene family occupies central positions in stress response networks throughout the animal kingdom and, as transcription factors, these proteins specify robust adaptive responses. Furthermore, the human counterpart is broadly implicated in age-related diseases including most cancers. Yet despite extensive characterization, disease deterrence by p53 is not well understood and conventional explanations for how p53 prevents oncogenic transformation have been fundamentally challenged. Since p53 genes are broadly conserved, ancestral properties of these genes offer promising routes towards understanding functions that become deranged in human diseases. Toward this goal, we built tools to explore the p53 regulatory network in genetic models, enabling unique opportunities to interrogate conserved properties that support human pathologies. These resources include in vivo biosensors that visualize real-time p53 action and complementation platforms that exchange human alleles for the fly counterpart. Leveraging these tools in flies and in fish, we discovered that p53 is acutely sensitive to - and normally restrains - retrotransposons, which are mobile elements broadly implicated in human disease. Likewise, we further showed that human p53 genes could similarly restrain transposons, but mutated p53 alleles from cancer patients could not. These combined discoveries suggest that p53 acts through highly conserved mechanisms to restrict transposons. Furthermore, since human p53 mutants are disabled for this activity, our findings raise the possibility that p53 mitigates disease, in part, by suppressing the activity of transposons. Consistent with this, we exposed hyperactive retrotransposons in p53-driven cancers and found co-repression activity that is obligate for p53 suppression. Initiatives advanced in this proposal build on these discoveries to determine precisely how p53 restrains mobile elements. Our approach integrates genetic models with molecular systems to deconstruct this process. Within this framework, we may deliver new opportunities for improved diagnosis and treatment of conditions fueled by dysfunctional p53.
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