P53 Genes Act to Restrain Mobile Elements

Oncogenic stress provokes tumor suppression by p53 but the extent to which this regulatory axis is conserved remains unknown. Using a biosensor to visualize p53 action, we find that Drosophila p53 is selectively active in gonadal stem cells after exposure to stressors that destabilize the genome. Similar p53 activity occurred in hyperplastic growths that were triggered either by the RasV12 oncoprotein or by failed differentiation programs. In a model of transient sterility, p53 was required for the recovery of fertility after stress, and entry into the cell cycle was delayed in p53- stem cells. Together, these observations establish that the stem cell compartment of the Drosophila germline is selectively licensed for stress-induced activation of the p53 regulatory network. Furthermore, the findings uncover ancestral links between p53 and aberrant proliferation that are independent of DNA breaks and predate evolution of the ARF/Mdm2 axis. While exploring the role of p53 in this context, we made a series of observations that justify a comprehensive examination of the relationship between p53 and transposon biology. Using Drosophila, zebrafish, and mouse models, we found that p53 functions to restrict the activity of retrotransposons. Furthermore, Drosophila p53 genetically interacted with components of the piRNA pathway and, in complementation studies, normal human p53 alleles restrained these mobile elements, but mutant p53 alleles from cancer patients could not. Consistent with these results, we also found patterns of unrestrained retrotransposons in p53-driven human cancers. Together, these observations indicate that ancestral functions of p53 operate through conserved mechanisms to suppress retrotransposons. Furthermore, since human p53 mutants are disabled for this activity, our findings raise the possibility that p53 mitigates oncogenic disease, in part, by restricting retrotransposon mobility.

Author dc:creator

• Wylie, Annika Dawn

Contributors dc:contributor

• Amatruda, James F.
• Abrams, John M.
• Hobbs, Helen H.
• Morrison, Sean J.

• Genes, p53
• Retroelements
• Tumor Suppressor Protein p53

Language dc:language

en

Identifier

1017760202

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/4461