Separase cleaves the kinetochore protein Meikin to direct the meiosis I/II transition

Abstract

To generate haploid gametes, meiotic cells must undergo two consecutive rounds of chromosome segregation without an intervening gap phase. Importantly, because homologous chromosomes are segregated in meiosis I, but sister chromatids are segregated in meiosis II, this requires a dramatic rewiring of the cell division machinery between the two divisions. How meiotic cells coordinate this rapid and substantial change to the cell division machinery is a central mystery at the heart of proper fertility and reproduction. Our work reveals a new paradigm that rewires key cell division processes at the meiosis I/II transition through the action of the protease Separase, which we demonstrate acts by cleaving the meiosis-specific kinetochore protein Meikin. Cleavage of Separase substrates such as cohesin results in their potent and complete inactivation.

In contrast, we find that Separase cleavage of Meikin acts as a molecular "scalpel," providing an elegant mechanism to precisely and irreversibly modulate Meikin activity between the two meiotic divisions without inactivating Meikin function. Our results demonstrate that the C-terminal Meikin cleavage product generated by Separase proteolysis retains substantial activity such that it localizes to kinetochores, binds to Plk1 kinase, and promotes downstream activities such as the cleavage of the meiosis-specific cohesin subunit Rec8, similar to full length Meikin. Importantly, we demonstrate that both the failure to cleave Meikin or the complete inactivation of Meikin at the meiosis I/II transition each result in dramatic defects in the proper execution of meiosis II. Our functional analysis in mouse oocytes demonstrates that precise Meikin cleavage is critical to differentially control meiosis I and II.

Thus, in contrast to previous models, Meikin is not just a regulator of meiosis I-specific activities, but differentially coordinates chromosome segregation across both meiotic divisions. Our discovery of Meikin as a new substrate for Separase cleavage represents a novel mechanism for the regulatory control of the meiosis I/II transition.