SummarySuccessful mitosis requires that cyclin B1:CDK1 kinase activity remains high until chromosomes are correctly aligned on the mitotic spindle. It has therefore been unclear why, in mammalian oocyte meiosis, cyclin B1 destruction begins before chromosome alignment is complete. Here, we resolve this paradox and show that mouse oocytes exploit an imbalance in the ratio of cyclin B1 to CDK1 to control CDK1 activity; early cyclin B1 destruction reflects the loss of an excess of non-CDK1-bound cyclin B1 in late prometaphase, while CDK1-bound cyclin B1 is destroyed only during metaphase. The ordered destruction of the two forms of cyclin B1 is brought about by a previously unidentified motif that is accessible in free cyclin B1 but masked when cyclin B1 is in complex with CDK1. This protects the CDK1-bound fraction from destruction in prometaphase, ensuring a period of prolonged CDK1 activity sufficient to achieve optimal chromosome alignment and prevent aneuploidy.
Human eggs frequently contain an incorrect number of chromosomes, a condition termed aneuploidy. Aneuploidy affects ∼10–25% of eggs in women in their early 30s, and more than 50% of eggs from women over 40. Most aneuploid eggs cannot develop to term upon fertilization, making aneuploidy in eggs a leading cause of miscarriages and infertility. The cellular origins of aneuploidy in human eggs are incompletely understood. Aneuploidy arises from chromosome segregation errors during the two meiotic divisions of the oocyte, the progenitor cell of the egg. Chromosome segregation is driven by a microtubule spindle, which captures and separates the paired chromosomes during meiosis I, and sister chromatids during meiosis II. Recent studies reveal that defects in the organization of the acentrosomal meiotic spindle contribute to human egg aneuploidy. The microtubules of the human oocyte spindle are very frequently incorrectly attached to meiotic kinetochores, the multi-protein complexes on chromosomes to which microtubules bind. Multiple features of human oocyte spindles favour incorrect attachments. These include spindle instability and many age-related changes in chromosome and kinetochore architecture. Here, we review how the unusual spindle assembly mechanism in human oocytes contributes to the remarkably high levels of aneuploidy in young human eggs, and how age-related changes in chromosome and kinetochore architecture cause aneuploidy levels to rise even higher as women approach their forties.
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.
Successful cell division relies on the faithful segregation of chromosomes. 13 If chromosomes segregate prematurely the cell is at risk of aneuploidy. Alternatively, 14 if cell division is attempted in the absence of complete chromosome segregation, non-15 segregated chromosomes can become trapped within the cleavage furrow and the cell 16 can lose viability. Securin plays a key role in this process, acting as a pseudosubstrate 17 to inhibit the protease separase that functions to cleave the cohesin rings that hold 18 chromosomes together. Consequently, securin must be depleted ahead of anaphase, 19 ensuring chromosome segregation occurs in time with the anaphase trigger. Here we 20 find that MI mouse oocytes contain a large excess of securin over separase and reveal 21 the existence of a novel mechanism that functions to promote the destruction of 22 excess securin in prometaphase. Critically, this mechanism relies on key residues that 23 are only exposed when securin is not bound to separase. We suggest that the majority 24 of non-separase bound securin is removed by this mechanism, allowing for separase 25 activity to be protected until just before anaphase. In addition, we further demonstrate 26 the importance of complementary mechanisms of separase inhibition by directly 27 measuring cleavage activity in live oocytes, confirming that both securin and 28 inhibition by cyclin B1-Cdk1 are independently sufficient to prevent premature 29 separase activation. 30 31 32 33 34 timed correctly. In situations where these events become disconnected, anaphase is 66 defective 23-25 . 67 In mitosis, the synchronous loss of cyclin B1 and securin is ensured by the similarity 68 of their destruction mechanisms. Both are ubiquitylated by the Anaphase Promoting 69 Complex/Cyclosome (APC/C) in metaphase 26,27 . Critically, this ubiquitylation relies 70 on both the availability of the APC/C activator protein Cdc20 and on a short linear 71 motif known as the D-box present in the N-terminus of both securin and cyclin B1 28-72 30 . Once all chromosomes are properly attached to spindle microtubules in metaphase, 73 Cdc20 and the APC/C form a bipartite receptor for D-box docking, triggering securin 74 and cyclin B1 destruction by the proteasome 31,32 . Prior to this, Cdc20 is sequestered 75 by the spindle assembly checkpoint (SAC), a diffusible signal generated at each 76 unattached kinetochore. The SAC functions to prevent docking of D-box motifs to the 77 APC/C and thereby inhibit anaphase until all chromosomes are attached to spindle 78 microtubules 33,34 . 79In contrast, securin and cyclin B1 destruction in mouse oocyte meiosis I is initiated in 80 prometaphase, prior to full chromosome alignment 35,36 . Initially this might seem like a 81 failure to ensure accurate chromosome segregation. However, our recent work 82 demonstrates that degradation of cyclin B1 in prometaphase is in fact a key feature of 83 a mechanism that functions to prevent aneuploidy in mouse oocytes 36 . At this time 84 point, destruction represents...
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