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APC/C-Cdh1-dependent anaphase and telophase progression during mitotic slippage

机译：有丝分裂滑移过程中依赖APC / C-Cdh1的后期和末期进展

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Background The spindle assembly checkpoint (SAC) inhibits anaphase progression in the presence of insufficient kinetochore-microtubule attachments, but cells can eventually override mitotic arrest by a process known as mitotic slippage or adaptation. This is a problem for cancer chemotherapy using microtubule poisons. Results Here we describe mitotic slippage in yeast bub2Δ mutant cells that are defective in the repression of precocious telophase onset (mitotic exit). Precocious activation of anaphase promoting complex/cyclosome (APC/C)-Cdh1 caused mitotic slippage in the presence of nocodazole, while the SAC was still active. APC/C-Cdh1, but not APC/C-Cdc20, triggered anaphase progression (securin degradation, separase-mediated cohesin cleavage, sister-chromatid separation and chromosome missegregation), in addition to telophase onset (mitotic exit), during mitotic slippage. This demonstrates that an inhibitory system not only of APC/C-Cdc20 but also of APC/C-Cdh1 is critical for accurate chromosome segregation in the presence of insufficient kinetochore-microtubule attachments. Conclusions The sequential activation of APC/C-Cdc20 to APC/C-Cdh1 during mitosis is central to accurate mitosis. Precocious activation of APC/C-Cdh1 in metaphase (pre-anaphase) causes mitotic slippage in SAC-activated cells. For the prevention of mitotic slippage, concomitant inhibition of APC/C-Cdh1 may be effective for tumor therapy with mitotic spindle poisons in humans.
机译：背景纺锤体装配检查点（SAC）在动粒体-微管附件不足的情况下会抑制后期进程，但细胞最终可能会通过称为有丝分裂的滑移或适应而克服有丝分裂的停滞。这是使用微管毒物进行癌症化学疗法的问题。结果在这里，我们描述了酵母bub2Δ突变细胞中的有丝分裂滑移，这些细胞在性早熟末期发作（有丝分裂出口）的抑制中存在缺陷。后期促进复合物/环体（APC / C）-Cdh1的早熟激活在存在诺考达唑的情况下导致有丝分裂滑移，而SAC仍然活跃。除有末期发作（有丝分裂退出）外，APC / C-Cdh1而非APC / C-Cdc20引发后期进展（安全蛋白降解，分离酶介导的粘着蛋白裂解，姐妹染色单体分离和染色体错聚），以及末期发作（有丝分裂退出）。这表明，不仅存在APC / C-Cdc20的抑制系统，而且对于APC / C-Cdh1的抑制系统，在动粒体-微管附件不足的情况下，对于精确的染色体分离都是至关重要的。结论在有丝分裂过程中APC / C-Cdc20依次激活为APC / C-Cdh1是精确有丝分裂的关键。 APC / C-Cdh1在中期（后期前）的过早激活会导致SAC激活细胞中的有丝分裂滑移。为了防止有丝分裂滑移，同时抑制APC / C-Cdh1可能对有丝分裂纺锤体中毒的肿瘤治疗有效。

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