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. Underscoring this point, the combined elimination of canonical p53 effectors (p21, Puma, Noxa) does not account for tumor suppression in mice. Furthermore, most p53 alleles seen in cancers are thought to harbor gain of function oncogenic activities that are also not known. Since p53 action is broadly conserved, our lab applies the Drosophila model to explore ancient features of this gene family that could provide novel entry points for understanding p53 in the context of human disease. In vertebrates and invertebrates, genotoxic stress leads to p53 activation. I used a biosensor to visualize p53 action in vivo and found that Drosophila p53 was selectively active in stem cells of the germ line after exposure to radiation. I also tested other genome destabilizers and found that deregulated retrotransposition similarly provoked robust p53 activity in this same stem cell compartment. Together, my observations established that stem cells of the germline are exclusively licensed for stress-induced p53 activity. Extending these studies, I also found compelling evidence suggesting that p53 acts to contain the mobilization of transposons in stem cells. Specifically, I discovered that p53-/- ovaries show massively elevated levels of transcript encoding the TAHRE retrotransposon. This phenotype was reversed in flies carrying a p53 rescue construct, allowing me to assign a new function to the p53 locus. Studies outlined in my proposal will expand upon this discovery. Specifically, I plan to verify and extend my results to ask whether other transposons are similarly affected. I will also examine the mechanism by p53 acts to contain transposons and identify the precise cells where this occurs. Importantly, I will also determine whether suppression of transposition by p53 is conserved in fish and in mice. Direct links between p53 function and transposon movement have not been reported, despite evidence that retrotransposition may be disregulated in some human cancers. My proposed studies could establish that p53 acts in conserved ways to inhibit the movement of transposons, providing a novel mechanism for understanding tumor suppression by this gene family.
The p53 gene is mutated in at least half of all human cancers but how this gene acts to suppress tumor formation is not well understood. Using a model system, I uncovered evidence suggesting that p53 may act to contain the movement of transposons. My studies could shed light on an unappreciated function for this gene family, raising the possibility that p53 acts to suppress tumor formation by suppressing the movement of transposons.