APC/C processivity and cell cycle regulation in meiosis I mouse oocytes

Phd ThesisAccurate cell division is a strictly ordered, highly regulated event. In mitosis, a robust spindle checkpoint ensures that chromosome division errors occur at a relatively low frequency, maintaining high levels of cyclin B1 and securin until chromosomes are accurately aligned. In contrast, in mouse oocytes, cyclin B1 and securin are targeted for destruction in late prometaphase I, at a time when the spindle is yet to fully migrate to the cortex and checkpoint proteins are still at kinetochores. This has been suggested to be symptomatic of an inefficient spindle checkpoint in meiosis I oocytes and a potential contributor to the high rates of aneuploidy observed in human oocytes. Curiously however, these observations have been made in mouse oocytes which ordinarily experience much lower rates of error. The seemingly early loss of cyclin B1 and securin rarely has a negative impact. This study demonstrates that cyclin B1 and securin destruction in late prometaphase I is not simply due to an inefficient spindle checkpoint, but instead due to controlled novel mechanisms of destruction within the oocyte. Meiotic cyclin B1 and securin destruction can in fact be split into two distinct periods; a later period that resembles mitotic destruction where the D-box is sufficient for APC/C targeting, and a much earlier period of destruction requiring previously unidentified motifs able to bypass the spindle checkpoint. Due to the location of these motifs, it is likely that they are hidden when in complex; cyclin B1 with Cdk1 and securin with separase. A model is proposed by which free pools of cyclin B1 and securin act as buffer zones, protecting Cdk1 activity and separase inhibition when the spindle checkpoint may become insufficient over the extended prometaphase period in the huge cell volume of an oocyte. Furthermore, meiotic cyclin A2 regulation is investigated. When put alongside cyclin B1 and securin data this begins to shed light on overall APC/C processivity in meiosis I