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.

Highlights

  • The p53 family of transcription factors is conserved throughout animal evolution [1,2]

  • Restricting CEP-1 to late pachytene cells is thought to ensure that apoptosis does not occur in cells at earlier stages of meiosis where meiotic recombination occurs

  • Through an unbiased genetic screen, we uncovered a role for the Ras/MAP kinase signaling pathway as a novel regulator of DNA damage–induced, CEP-1–dependent apoptosis

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Summary

Introduction

The p53 family of transcription factors is conserved throughout animal evolution [1,2]. In vertebrates the founding member, p53, is a key tumour suppressor and is the most commonly mutated gene in human tumours. Based on sequence similarity it appears that the majority of invertebrate p53 family members are most closely related to mammalian p63 and it has been postulated that an ancient function of the p53 family might be the regulation of germ cell apoptosis [4]. The sole C. elegans p53 homologue CEP-1 was implicated in regulating germ cell apoptosis in response to DNA damage and meiotic recombination failure [5,6]. More recent reports indicate that the TAp63 specific isoform is required to eliminate damaged meiotic germ cells in the mammalian female germline [4]

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