The Christopher Chen Oocyte Biology Research Laboratory, UQ Centre for Clinical Research, The University of Queensland, Herston 4029, QLD, Australia.
Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
J Cell Sci. 2019 Sep 26;132(18):jcs233379. doi: 10.1242/jcs.233379.
During mitosis, anaphase is triggered by anaphase-promoting complex (APC)-mediated destruction of securin and cyclin B1, which leads to inactivation of cyclin-dependent kinase 1 (Cdk1). By regulating APC activity, the mitotic spindle assembly checkpoint (SAC) therefore has robust control over anaphase timing to prevent chromosome mis-segregation. Mammalian oocytes are prone to aneuploidy, the reasons for which remain obscure. In mitosis, Cep55 is required post-anaphase for the final steps of cytokinesis. We found that Cep55-depleted mouse oocytes progress normally through early meiosis I, but that anaphase I fails as a result of persistent Cdk1 activity. Unexpectedly, Cdk1 inactivation was compromised following Cep55 depletion, despite on-time SAC silencing and intact APC-mediated proteolysis. We found that impaired Cdk1 inactivation was caused by inadequate inhibitory Cdk1 phosphorylation consequent upon failure to suppress Cdc25 phosphatase, identifying a proteolysis-independent step necessary for anaphase I. Thus, the SAC in oocytes does not exert exclusive control over anaphase I initiation, providing new insight into vulnerability to error.
在有丝分裂过程中，后期被后期促进复合物（APC）介导的securin 和 cyclin B1 的破坏所触发，这导致细胞周期蛋白依赖性激酶 1（Cdk1）失活。通过调节 APC 活性，因此有丝分裂纺锤体组装检查点（SAC）对后期时间具有强大的控制作用，以防止染色体错误分离。哺乳动物卵母细胞容易发生非整倍体，其原因尚不清楚。在有丝分裂中， Cep55 在胞质分裂的最后步骤中需要在后后期。我们发现，Cep55 耗尽的小鼠卵母细胞正常通过早期减数分裂 I 进行，但由于 Cdk1 活性持续存在，后期 I 失败。出乎意料的是，尽管 SAC 沉默及时且 APC 介导的蛋白水解完整，但 Cep55 耗尽后 Cdk1 失活受损。我们发现，Cdk1 失活受损是由于未能抑制 Cdc25 磷酸酶，导致抑制性 Cdk1 磷酸化不足引起的，这确定了后期 I 所必需的一个与蛋白水解无关的步骤。因此，卵母细胞中的 SAC 对后期 I 的启动并非具有排他性的控制作用，这为错误的易感性提供了新的见解。
