p53 genes function to restrain mobile elements
- Annika Wylie1,
- Amanda E. Jones1,
- Alejandro D'Brot1,
- Wan-Jin Lu2,
- Paula Kurtz1,
- John V. Moran3,4,5,
- Dinesh Rakheja6,7,
- Kenneth S. Chen6,
- Robert E. Hammer8,
- Sarah A. Comerford9,
- James F. Amatruda6,10,11 and
- John M. Abrams1
- 1Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 2Stanford University Medical Center, Stanford, California 94305, USA;
- 3Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48019, USA;
- 4Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48019, USA;
- 5Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan 48019, USA;
- 6Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 7Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 8Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 9Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 10Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 11Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
- Corresponding author: john.abrams{at}utsouthwestern.edu
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.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.266098.115.
- Received May 21, 2015.
- Accepted November 23, 2015.
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