A prometaphase mechanism of securin destruction is essential for meiotic progression in mouse oocytes

Christopher Thomas,Suzanne Madgwick,Rebecca J Harris,Scott T Kerridge,Mark D Levasseur,Jonathan M G Higgins,Benjamin Wetherall,Owen R Davies

doi:10.1038/s41467-021-24554-2

Abstract

Successful cell division relies on the timely removal of key cell cycle proteins such as securin. Securin inhibits separase, which cleaves the cohesin rings holding chromosomes together. Securin must be depleted before anaphase to ensure chromosome segregation occurs with anaphase. Here we find that in meiosis I, mouse oocytes contain an excess of securin over separase. We reveal a mechanism that promotes excess securin destruction in prometaphase I. Importantly, this mechanism relies on two phenylalanine residues within the separase-interacting segment (SIS) of securin that are only exposed when securin is not bound to separase. We suggest that these residues facilitate the removal of non-separase-bound securin ahead of metaphase, as inhibiting this period of destruction by mutating both residues causes the majority of oocytes to arrest in meiosis I. We further propose that cellular securin levels exceed the amount an oocyte is capable of removing in metaphase alone, such that the prometaphase destruction mechanism identified here is essential for correct meiotic progression in mouse oocytes.

Highlights

Successful cell division relies on the timely removal of key cell cycle proteins such as securin
We present evidence that non-separase-bound securin is targeted for degradation by a previously unidentified destruction mechanism that is essential for correct meiotic progression
Securin is destroyed alongside cyclin B1 and only in metaphase, once the spindle checkpoint is inactivated in response to correct attachment of all kinetochores to microtubules[4,33]

Summary

Introduction

Successful cell division relies on the timely removal of key cell cycle proteins such as securin. Both are ubiquitinated by the APC/C during metaphase[4,33] This degradation relies on both the availability of the APC/C coactivator protein Cdc[20] and on the D-box motif present within the N-terminus of both securin and cyclin B134–36. The SAC functions to block the formation of the APC/C-Cdc[20] bipartite D-box receptor, preventing securin and cyclin B1 destruction until all chromosomes are attached to spindle microtubules[38,39,40]. Where APC/C substrates must be targeted prior to metaphase alignment, additional motifs are present that function to bypass the SAC One example of this is the ABBA motif in cyclin A, which directly outcompetes SAC protein binding of Cdc2041,42. The ABBA motif in cyclin A permits Dbox-dependent degradation in prometaphase during an active SAC

Methods

Results

Conclusion