CSN5/Jab1 regulates early oogenesis by ubiquitin-dependent degradation of cyclin E. S.K. Beckendorf , S. Doronkin , I. Djagaeva. Dept Molecular & Cell Biol, Univ California, Berkeley, CA.

   In early oogenesis the mitotic cell cycle is precisely controlled to produce 16 cell germ line cysts. Alteration of cell cycle regulators can lead to premature mitotic arrest or to unrestrained proliferation and ovarian tumors. Here we show that mutations in CSN5/Jab1, a subunit of the COP9 signalosome (CSN), disrupt ovarian development and cause abnormal cystocyte divisions, defects in oocyte/nurse cell fate, and apoptosis. The CSN is a conserved 8 subunit complex that regulates ubiquitin-dependent protein degradation via the proteosome. We found that CSN5-mutant cells have elevated levels of Cyclin E and show inhibition or arrest of cell proliferation and enlarged, polyploid nuclei. CSN4 mutants have a similar phenotype, suggesting that the entire CSN, rather than free CSN5, is required for Cyclin E regulation. Pulse-chase experiments demonstrated that degradation of ectopic Cyclin E is CSN5 dependent. Next we showed that CSN5 acts through the SCF (Skp1-Cullin1-F-box) ubiquitin ligase complex to target Cyclin E. In either CSN5 or CSN4 mutants Cullin1 accumulates in a Nedd8-modified form, suggesting that removal of the ubiquitin-like protein Nedd8 from Cullin1 is required for the degradation process. Further linking CSN5 to Cullin1 and the SCF complex, we found that both Nedd8 and Cullin1/lin19 germline clones arrest early in oogenesis, and Cullin1/lin19 mutants interact dominantly with both CSN5 and CSN4 mutants. F-box proteins link the SCF to particular targets for ubiquitination and degradation. We found that germline clones mutant for the F-box protein Archipelago autonomously accumulate Cyclin E. Furthermore, both CSN5 and CSN4 mutations interact dominantly with archipelago mutations to disrupt germline mitosis. In summary, we have shown for the first time that the CSN regulates Cyclin E degradation. In addition, we demonstrate that this regulation acts through the SCF-ubiquitin ligase complex and the specific F-box protein Archipelago.