Functional activation of P53 by reverse transcriptase processes

The National Institute of General Medical Sciences, part of the National Institutes of Health within the Department of Health and Human Services, awarded Southern Methodist University $380,626 on August 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859).

The award funds research into functional activation of P53 by reverse transcriptase processes, with emphasis on P53's role in suppressing retrotransposons—mobile genetic elements implicated in human disease. The investigator applies the Drosophila model to explore conserved P53 functions across the animal kingdom. Prior work demonstrated that wild-type P53 suppresses retrotransposon activity while cancer-patient-derived P53 mutants fail to do so, and that unrestrained retrotransposons appear in P53-driven mouse and human cancers. The funded studies will expand this research to determine the biological importance of P53-mediated transposon repression and establish the precise mechanisms involved, with the long-term goal of identifying novel entry points for understanding P53 in human disease and cancer prevention.

Work is performed at Southern Methodist University in Dallas, Texas, with a period of performance through March 31, 2031. This is a Project Grant, the assistance type used by NIGMS for investigator-initiated basic research awards.

Abstract

P53 is commonly mutated in human cancers but, despite extensive research, we still lack a complete understanding of how this protein functions to suppress tumors. Since P53 is broadly conserved across the animal kingdom, my lab applies the drosophila model to explore ancient features of this gene family, which could provide novel entry points for understanding P53 in the context of human disease. By studying the germline cells of flies and fish, we discovered that P53 exerts conserved functions to restrain a class of mobile genetic elements called retrotransposons, which are broadly implicated in human disease. We also showed that P53 is acutely responsive when these transposons are dysregulated and, in complementation studies, human P53 genes suppressed transposons but mutant P53 alleles from cancer patients could not. Consistent with these observations, we also found patterns of unrestrained retrotransposons in P53-driven mouse and human cancers. Together, our recent progress implicates retrotransposons as forces that shaped the evolution of P53 function. Importantly, our work also offers a novel hypothesis for cancer prevention by P53, whereby P53 may mitigate oncogenic disease, in part, by restricting transposon activity. Studies outlined in my proposal will expand upon these discoveries using the drosophila model. My long-term goals are to determine the biological importance of P53-mediated transposon repression and establish the precise mechanisms involved. Since transposon repression by P53 may be important for tumor suppression, our findings could provide novel entry points for understanding P53 in the context of human disease.