Maternal age-dependent APC/C-mediated decrease in securin causes premature sister chromatid separation in meiosis II

Nabti, Ibtissem; Grimes, R.M.; Sarna, Hema; Marangos, Petros; Carroll, John

doi:10.1038/ncomms15346

Cited by 49 publications

(41 citation statements)

References 44 publications

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“…It was subsequently found that metaphase-II eggs from aged mice exhibit lower levels of securin, and that this reduction is likely explained by the loss of the SAC activity, which would normally moderate the Anaphase-Promoting-Complex/Cyclosome at the meiosis-I to meiosis-II transition. Accordingly, overexpression of securin in aged oocytes was able to partially prevent premature separation of sisters [124]. This striking observation potentially places a SAC deficiency upstream of the cohesion loss that is central to oocyte aneuploidy.…”

Section: Sac Decline?mentioning

confidence: 88%

Segregating Chromosomes in the Mammalian Oocyte

Mihajlović

FitzHarris

2018

Current Biology

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Chromosome segregation errors in human oocytes lead to aneuploid embryos that cause infertility and birth defects. Here we provide an overview of the chromosome-segregation process in the mammalian oocyte, highlighting mechanistic differences between oocytes and somatic cells that render oocytes so prone to segregation error. These differences include the extremely large size of the oocyte cytoplasm, the unique geometry of meiosis-I chromosomes, idiosyncratic function of the spindle assembly checkpoint, and dramatically altered oocyte cell-cycle control and spindle assembly, as compared to typical somatic cells. We summarise recent work suggesting that aging leads to a further deterioration in fidelity of chromosome segregation by impacting multiple components of the chromosome-segregation machinery. In addition, we compare and contrast recent results from mouse and human oocytes, which exhibit overlapping defects to differing extents. We conclude that the striking propensity of the oocyte to mis-segregate chromosomes reflects the unique challenges faced by the spindle in a highly unusual cellular environment.

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Section: Sac Decline?mentioning

confidence: 88%

Segregating Chromosomes in the Mammalian Oocyte

Mihajlović

FitzHarris

2018

Current Biology

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“…Indeed Nabti et al revealed that oocytes from aged mice destroy securin more rapidly and to a greater extent than oocytes from younger mice. As a consequence, separase inhibition in MII is incomplete in these cells and sister chromatid cohesion is lost prematurely resulting in segregation defects 57 .…”

Section: Discussionmentioning

confidence: 99%

Synchronous chromosome segregation in mouse oocytes is ensured by biphasic securin destruction and cyclin B1-Cdk1

Thomas

Levasseur

Harris

et al. 2019

Preprint

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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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“…A recent study indicates that Smc1β is essential for activation of SAC activity during mouse oocyte meiosis [ 62 ]. Therefore, there might be some association between decreased kinetochore localization of the SAC proteins and cohesion loss with maternal age, including the possibility that decreased SAC ability in aged oocytes promotes the APC/C Cdc20 to degrade cyclin B1 and securin, which causes the loss of sister chromatid cohesion [ 63 ] ( Figure 2 A).…”

Section: The Cause Of Age-related Loss Of Cohesionmentioning

confidence: 99%

Age-Related Loss of Cohesion: Causes and Effects

Cheng

Liu

2017

IJMS

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Aneuploidy is a leading genetic cause of birth defects and lower implantation rates in humans. Most errors in chromosome number originate from oocytes. Aneuploidy in oocytes increases with advanced maternal age. Recent studies support the hypothesis that cohesion deterioration with advanced maternal age represents a leading cause of age-related aneuploidy. Cohesin generates cohesion, and is established only during the premeiotic S phase of fetal development without any replenishment throughout a female’s period of fertility. Cohesion holds sister chromatids together until meiosis resumes at puberty, and then chromosome segregation requires the release of sister chromatid cohesion from chromosome arms and centromeres at anaphase I and anaphase II, respectively. The time of cohesion cleavage plays an important role in correct chromosome segregation. This review focuses specifically on the causes and effects of age-related cohesion deterioration in female meiosis.

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Maternal age-dependent APC/C-mediated decrease in securin causes premature sister chromatid separation in meiosis II

Cited by 49 publications

References 44 publications

Segregating Chromosomes in the Mammalian Oocyte

Segregating Chromosomes in the Mammalian Oocyte

Synchronous chromosome segregation in mouse oocytes is ensured by biphasic securin destruction and cyclin B1-Cdk1

Age-Related Loss of Cohesion: Causes and Effects

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