Tumor Suppression and Transposopathy

Tahre deregulation FISH
In p53-/- ovaries, TAHRE accumulates in the germ plasm

In humans, p53 is altered in most human cancers but, despite extensive characterization, precisely how p53 acts to suppress tumors remains poorly understood. By exposing ancestral properties of p53, we hope to illuminate why this tumor suppressor becomes deranged in human cancers. Toward this objective, we built innovative tools to interrogate p53 function in the Drosophila and zebrafish systems and, leveraging these, we discovered that p53 tonically acts to suppress transposons.

Furthermore, in ‘humanized’ p53 fly strains (that exchange fly p53 for human counterparts) normal human p53 genes contained transposons but mutant alleles arising in cancer patients cannot. Taken together, these discoveries suggest that p53 acts through highly conserved mechanisms to repress transposons and suggest that p53 suppresses oncogenic disease, in part, by restraining mobile elements.

Wilms tumor ORF1 stain
Wilms tumors mutant for p53 show elevated human LINE1 ORF1p expression

We believe these insights may help explain why p53 defects are permissive for cancers and might also explain the instability that characterizes most cancer genomes. Consistent with these ideas, we uncovered direct evidence for unrestrained retrotransposons in p53-mutant mouse cancer models and in genotyped patient tumors cancers.

These insights open opportunities to examine the ‘transposopathy’ hypothesis as a general principle in p53 biology.