Cdc20 and Cdh1 are the activating subunits of the anaphase-promoting complex (APC), an E3 ubiquitin ligase that drives cells into anaphase by inducing degradation of cyclin B and the anaphase inhibitor securin1. To prevent chromosome missegregation, APC activity directed against these mitotic regulators must be inhibited until all chromosomes are properly attached to the mitotic spindle2. Here we show that in mitosis timely destruction of securin by APC is regulated by the nucleocytoplasmic transport factors Rae1 and Nup98. We show that combined Rae1 and Nup98 haploinsufficiency in mice results in premature separation of sister chromatids, severe aneuploidy and untimely degradation of securin. We find that Rae1 and Nup98 form a complex with Cdh1-activated APC (APCCdh1) in early mitosis and specifically inhibit APCCdh1-mediated ubiquitination of securin. Dissociation of Rae1 and Nup98 from APC coincides with the release of the mitotic checkpoint protein BubR1 from Cdc20-activated APC (APCCdc20) at the metaphase to anaphase transition. Together, our results suggest that Rae1 and Nup98 are temporal regulators of APCCdh1 that maintain euploidy by preventing unscheduled degradation of securin.
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