57 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)64-77
Number of pages14
JournalGenes and Development
Volume30
Issue number1
DOIs
StatePublished - Jan 1 2016

Fingerprint

p53 Genes
Retroelements
Neoplasms
Long Interspersed Nucleotide Elements
Alleles
Zebrafish
Small Interfering RNA
Genetic Recombination
Genes
Drosophila
Chromatin

Keywords

  • Drosophila
  • Human cancers
  • Mouse cancer models
  • p53
  • PiRNAs
  • Retrotransposons
  • Zebrafish

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Wylie, A., Jones, A. E., D’Brot, A., Lu, W. J., Kurtz, P., Moran, J. V., ... Abrams, J. M. (2016). p53 genes function to restrain mobile elements. Genes and Development, 30(1), 64-77. https://doi.org/10.1101/gad.266098.115

p53 genes function to restrain mobile elements. / Wylie, Annika; Jones, Amanda E.; D’Brot, Alejandro; Lu, Wan Jin; Kurtz, Paula; Moran, John V.; Rakheja, Dinesh; Chen, Kenneth; Hammer, Robert E; Comerford, Sarah A; Amatruda, James F; Abrams, John M.

In: Genes and Development, Vol. 30, No. 1, 01.01.2016, p. 64-77.

Research output: Contribution to journalArticle

Wylie A, Jones AE, D’Brot A, Lu WJ, Kurtz P, Moran JV et al. p53 genes function to restrain mobile elements. Genes and Development. 2016 Jan 1;30(1):64-77. https://doi.org/10.1101/gad.266098.115
Wylie, Annika ; Jones, Amanda E. ; D’Brot, Alejandro ; Lu, Wan Jin ; Kurtz, Paula ; Moran, John V. ; Rakheja, Dinesh ; Chen, Kenneth ; Hammer, Robert E ; Comerford, Sarah A ; Amatruda, James F ; Abrams, John M. / p53 genes function to restrain mobile elements. In: Genes and Development. 2016 ; Vol. 30, No. 1. pp. 64-77.
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