Aneuploidy in Oocytes Is Prevented by Sustained CDK1 Activity through Degron Masking in Cyclin B1

Levasseur, Mark; Thomas, Christopher; Davies, Owen R.; Higgins, Jonathan M.G.; Madgwick, Suzanne

doi:10.1016/j.devcel.2019.01.008

Cited by 41 publications

(41 citation statements)

References 66 publications

(99 reference statements)

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“…In mouse oocytes, cyclin B1 is destroyed by a two-step mechanism; an initial period of prometaphase destruction requires both a D-box and an additional motif (the PM motif). This is followed by a second period of destruction as the D-box becomes sufficient once the SAC is satisfied in metaphase 36 . Given that securin and cyclin B1 destruction is synchronous in oocytes, we reasoned that securin may also be destroyed by a similar mechanism 35,36 .…”

Section: Resultsmentioning

confidence: 99%

“…This is followed by a second period of destruction as the D-box becomes sufficient once the SAC is satisfied in metaphase 36 . Given that securin and cyclin B1 destruction is synchronous in oocytes, we reasoned that securin may also be destroyed by a similar mechanism 35,36 . To test this, we initially designed and tested two fluorescent reporters; full-length securin (securin FL) and the N-terminal 101 residues (securin N101).…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, securin and cyclin B1 destruction in mouse oocyte meiosis I is initiated in prometaphase, prior to full chromosome alignment 35,36 . Initially this might seem like a failure to ensure accurate chromosome segregation.…”

Section: Introductionmentioning

confidence: 91%

“…Initially this might seem like a failure to ensure accurate chromosome segregation. However, our recent work demonstrates that degradation of cyclin B1 in prometaphase is in fact a key feature of a mechanism that functions to prevent aneuploidy in mouse oocytes 36 . At this time point, destruction represents only the loss of non-Cdk1-bound cyclin B1.…”

Section: Introductionmentioning

confidence: 95%

“…By this strategy, an excess of cyclin B1 acts as an APC/C decoy to maintain Cdk1 activity and prolong prometaphase in oocyte meiosis I. This is critical in mouse oocytes since, in the absence of excess cyclin B1, spindle checkpoint activity is insufficient in preventing anaphase for long enough to fully align chromosomes, a process that takes hours rather than the tens of minutes to complete mitosis 36 .…”

Section: Introductionmentioning

confidence: 99%

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

Thomas

Levasseur

Harris

et al. 2019

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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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Section: Resultsmentioning

confidence: 99%