Precise control of the transition from self-renewal to terminal differentiation in stem cells is critical to maintain a balance between cell populations: an excess of stem cell self-renewal can lead to tumourigenesis, whereas an excess of differentiation can deplete the stem-cell pool. In the adult Caenorhabditis elegans germline, Notch signals emanate from the somatic distal tip cell to maintain germline stem cells (GSCs) in a proliferative state by repressing the translation of meiotic promoting factors. We have uncovered a novel pathway regulating the decision between GSC renewal and meiotic differentiation that involves the ubiquitin-proteolytic system (UPS). Using a novel temperature-sensitive allele of the cul-2 gene, we found that the CUL-2 RING E3 ubiquitin ligase, in combination with the Leucine Rich Repeat 1 substrate recognition subunit (CRL2LRR-1), negatively regulates the transition from the mitotic zone of the germline to the meiotic programme of chromosome pairing, synapsis, and recombination. More specifically, we find that CRL2LRR-1 regulates in stem cells the stability of the HORMA domain-containing protein HTP-3, which is required for loading structural proteins onto meiotic chromosomes and for the formation of the double-strand breaks that initiate meiotic recombination. Furthermore, we found that cyclin E/Cdk2 kinase, which is specifically activated in GSCs but repressed upon meiotic differentiation, phosphorylates HTP-3 and regulates its stability. Besides HTP-3, CUL-2 targets other factors for degradation to prevent precocious meiotic entry and to promote germline stem cell proliferation. Herein, we propose to use a unique combination of genetics, cell biology, biochemical and quantitative proteomic approaches to elucidate the role of protein degradation in germ cell biology. In particular, we propose to identify CUL-2 targets in the germline and the molecular mechanisms controlling their degradation in space. The role of the UPS and CUL-2 in germline stem cell biology has not been studied so far. CUL-2 is evolutionarily conserved in metazoans and appears to regulate germ cell divisions in Drosophila. Therefore emerging paradigms provided by the study of germ cell biology in C. elegans should be directly applicable in other systems and possibly also in humans.