A Kinetochore-Associated Proteasome Pool Drives a Second Pathway of Cohesin Removal during Meiosis

Chromosome segregation necessitates precise removal of sister chromatid cohesion, a process that hinges on the cleavage of cohesin by the protease separase. This separase activation, in turn, relies on the destruction of the inhibitor securin by the ubiquitin-proteasome system (UPS) and phosphorylation of the cohesin kleisin subunit.

Until now, the role of the UPS in cohesin priming has been uncertain. However, researchers have now discovered that the 26S proteasome plays a crucial role in cohesin removal during meiosis II through two parallel pathways. By utilizing mutants that disrupt either the proteasome core or its regulatory particles, the team identified a proteasome function that is essential for centromeric cohesin removal during meiosis II, but not for separase activation.

When this specific proteasome function is impaired, it leads to the accumulation of phosphatase anchor shugoshin (Sgo1) at centromeres, impaired cleavage of meiotic kleisin Rec8, and frequent failure in sister chromatid segregation. Interestingly, bypassing the need for Rec8 priming, either by using a phosphomimetic rec8 allele or by enabling Rec8 cleavage independently of separase, restores normal chromosome segregation.

This indicates that the proteasome independently mediates cohesin removal, not merely by activating separase.

Supporting this direct role, proteasomes were found to accumulate prominently at kinetochores during meiosis II. These findings establish the proteasome as a dual-function regulator, responsible for both separase activation and cohesin priming. They unveil how a single proteolytic machine orchestrates the two sequential molecular pathways necessary for stepwise chromosome segregation during meiosis.