Regulation of caenorhabditis elegans p53/cep-1-dependent germ cell apoptosis by ras/mapk signaling

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. © 2011 rutkowski et al.