# Suppression of mobile elements by p53 genes

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $344,400

## Abstract

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.

## Key facts

- **NIH application ID:** 10742927
- **Project number:** 5R01GM115682-08
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** John M Abrams
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $344,400
- **Award type:** 5
- **Project period:** 2015-08-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10742927

## Citation

> US National Institutes of Health, RePORTER application 10742927, Suppression of mobile elements by p53 genes (5R01GM115682-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10742927. Licensed CC0.

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