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Regulation of Caenorhabditis elegans p53/CEP-1-Dependent Germ Cell Apoptosis by Ras/MAPK Signaling

Regulation of Caenorhabditis elegans p53/CEP-1-Dependent Germ Cell Apoptosis by Ras/MAPK Signaling

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Authors

  • Rachael Rutkowski
  • Robin Dickinson
  • Graeme Stewart
  • Ashley Craig
  • Marianne Schimpl
  • Stephen M. Keyse
  • Anton Gartner (Lead / Corresponding author)

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Original languageEnglish
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Pages-
Number of pages21
JournalPLoS Genetics
Journal publication dateAug 2011
Journal number8
Volume7
DOIs
StatePublished

Abstract

Maintaining genome stability in the germline is thought to be an evolutionarily ancient role of the p53 family. The sole Caenorhabditis elegans p53 family member CEP-1 is required for apoptosis induction in meiotic, late-stage pachytene germ cells in response to DNA damage and meiotic recombination failure. In an unbiased genetic screen for negative regulators of CEP-1, we found that increased activation of the C. elegans ERK orthologue MPK-1, resulting from either loss of the lip-1 phosphatase or activation of let-60 Ras, results in enhanced cep-1-dependent DNA damage induced apoptosis. We further show that MPK-1 is required for DNA damage-induced germ cell apoptosis. We provide evidence that MPK-1 signaling regulates the apoptotic competency of germ cells by restricting CEP-1 protein expression to cells in late pachytene. Restricting CEP-1 expression to cells in late pachytene is thought to ensure that apoptosis doesn't occur in earlier-stage cells where meiotic recombination occurs. MPK-1 signaling regulates CEP-1 expression in part by regulating the levels of GLD-1, a translational repressor of CEP-1, but also via a GLD-1-independent mechanism. In addition, we show that MPK-1 is phosphorylated and activated upon ionising radiation (IR) in late pachytene germ cells and that MPK-1-dependent CEP-1 activation may be in part direct, as these two proteins interact in a yeast two-hybrid assay. In summary, we report our novel finding that MAP kinase signaling controls CEP-1-dependent apoptosis by several different pathways that converge on CEP-1. Since apoptosis is also restricted to pachytene stage cells in mammalian germlines, analogous mechanisms regulating p53 family members are likely to be conserved throughout evolution.

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