The SCFFSN-1 ubiquitin ligase controls germline apoptosis through CEP-1/p53 in C. elegans

The nematode Caenorhabditis elegans contains a single ancestral p53 family member, cep-1 , which is required to activate apoptosis of germ cells in response to DNA damage. To understand how the cep-1 /p53 pathway is regulated in response to genotoxic stress, we performed an RNA interference screen and identified the neddylation pathway and components of an SCF (Skp1/cullin/F-box) E3 ubiquitin ligase as negative regulators of cep-1 -dependent germ cell apoptosis. Here, we show that the cullin gene cul-1 , the Skp1-related gene skr-1 , and the ring box genes rbx-1 and rpm-1 all negatively regulate cep-1 -dependent germ cell apoptosis in response to the DNA-alkylating agent N -ethyl- N -nitrosourea (ENU). We also identified the F-box protein FSN-1, previously shown to form an SCF ligase that regulates synapse development, as a negative regulator of cep-1 -dependent germline apoptosis. The hypersensitivity of fsn-1 mutants to ENU-induced germline apoptosis was completely suppressed by a cep-1 loss-of-function allele. We further provide evidence that the transcriptional activity, phosphorylation status, and levels of endogenous CEP-1 are higher in fsn-1 mutants compared with wild-type animals after ENU treatment. Our results uncover a novel role for the SCF FSN-1 E3 ubiquitin ligase in the regulation of cep-1 -dependent germ cell apoptosis.