title: p53 genes function to restrain mobile elements.
abstract: 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.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: Annika
authors.initials: A
authors.lastname: Wylie
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Jones
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: Alejandro
authors.initials: A
authors.lastname: D'Brot
authors.affiliation: Stanford University Medical Center, Stanford, California 94305, USA;
authors.forename: Wan-Jin
authors.initials: WJ
authors.lastname: Lu
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: Paula
authors.initials: P
authors.lastname: Kurtz
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48019, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48019, USA; Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan 48019, USA;
authors.forename: John V
authors.initials: JV
authors.lastname: Moran
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: Dinesh
authors.initials: D
authors.lastname: Rakheja
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hammer
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Comerford
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Amatruda
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: John M
authors.initials: JM
authors.lastname: Abrams
mesh_terms: D000818:Animals; D004330:Drosophila / Q000235:genetics; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics; D018626:Retroelements / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics
chemical_list: D018626:Retroelements; D016159:Tumor Suppressor Protein p53
keywords: Drosophila; human cancers; mouse cancer models; p53; piRNAs; retrotransposons; zebrafish