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.