RESUMO
Throughout the animal kingdom, p53 genes govern stress response networks by specifying adaptive transcriptional responses. The human member of this gene family is mutated in most cancers, but precisely how p53 functions to mediate tumor suppression is not well understood. Using Drosophila and zebrafish models, we show that p53 restricts retrotransposon activity and genetically interacts with components of the piRNA (piwi-interacting RNA) pathway. Furthermore, transposon eruptions occurring in the p53(-) germline were incited by meiotic recombination, and transcripts produced from these mobile elements accumulated in the germ plasm. In gene complementation studies, normal human p53 alleles 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. Furthermore, p53 status correlated with repressive chromatin marks in the 5' sequence of a synthetic LINE-1 element. Together, these observations indicate that ancestral functions of p53 operate through conserved mechanisms to contain retrotransposons. Since human p53 mutants are disabled for this activity, our findings raise the possibility that p53 mitigates oncogenic disease in part by restricting transposon mobility.
Assuntos
Genes p53/genética , Retroelementos/fisiologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Animais , Drosophila/genética , Feminino , Variação Genética , Humanos , Masculino , Camundongos , Mutação/genética , Neoplasias/genética , Retroelementos/genética , Peixe-Zebra/genéticaRESUMO
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 Ras(V12) 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. DOI: http://dx.doi.org/10.7554/eLife.01530.001.
Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Ovário/metabolismo , Nicho de Células-Tronco , Células-Tronco/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Técnicas Biossensoriais , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Dano ao DNA , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Feminino , Fertilidade , Regulação da Expressão Gênica , Instabilidade Genômica , Infertilidade/genética , Infertilidade/metabolismo , Infertilidade/fisiopatologia , Ovário/patologia , Ovário/fisiopatologia , Transdução de Sinais , Células-Tronco/patologia , Estresse Fisiológico , Fatores de Tempo , Proteína Supressora de Tumor p53/genéticaRESUMO
It is now well appreciated that the apoptosome, which governs caspase-dependent cell death, also drives nonapoptotic caspase activation to remodel cells. However, the determinants that specify whether the apoptosome acts to kill or remodel have yet to be identified. Here we report that Tango7 collaborates with the Drosophila apoptosome to drive a caspase-dependent remodeling process needed to resolve individual sperm from a syncytium. In these cells, Tango7 is required for caspase activity and localizes to the active apoptosome compartment via its C terminus. Furthermore, Tango7 directly stimulates the activity of this complex in vitro. We propose that Tango7 specifies the Drosophila apoptosome as an effector of cellular remodeling.
