During mitotic chromosome segregation, the protease separase severs cohesin between sister chromatids. A probe for separase activity has shown that separase undergoes abrupt activation shortly before anaphase onset, after being suppressed throughout metaphase; however, the relevance of this control remains unclear. Here, we report that separase activates precociously, with respect to anaphase onset, during prolonged metaphase in multiple types of cancer cell lines. The artificial extension of metaphase in chromosomally stable diploid cells leads to precocious activation and, subsequently, to chromosomal bridges in anaphase, which seems to be attributable to incomplete cohesin removal. Conversely, shortening back of a prolonged metaphase restores the activation of separase and ameliorates anaphase bridge formation. These observations suggest that retarded metaphase progression affects the separase activation profile and its enzymatic proficiency. Our findings provide an unanticipated etiology for chromosomal instability in cancers and underscore the relevance of swift mitotic transitions for fail-safe chromosome segregation.

在有丝分裂染色体分离过程中，蛋白酶分离酶切断姐妹染色单体之间的粘着蛋白。对分离酶活性的研究表明，分离酶在后期开始前不久经历突然激活，在整个中期被抑制之后；然而，这种控制的相关性仍不清楚。在这里，我们报告分离酶在多种类型的癌细胞系中，在延长中期期间，就后期开始而言，早熟激活。染色体稳定的二倍体细胞中中期的人工延伸导致早熟激活，随后导致后期的染色体桥，这似乎归因于不完全的粘连蛋白去除。相反，延长中期的缩短恢复了分离酶的激活并改善了后期桥的形成。这些观察结果表明，延迟的中期进展会影响分离酶活化谱及其酶的熟练程度。我们的研究结果为癌症中的染色体不稳定性提供了意想不到的病因，并强调了快速有丝分裂转变与故障安全染色体分离的相关性。