The Rae1-Nup98 complex prevents aneuploidy by inhibiting securin degradation.
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 securin. To prevent chromosome missegregation, APC activity directed against these mitotic regulators must be inhibited until all chromosomes are properly attached to the mitotic spindle. 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 (APC(Cdh1)) in early mitosis and specifically inhibit APC(Cdh1)-mediated ubiquitination of securin. Dissociation of Rae1 and Nup98 from APC(Cdh1) coincides with the release of the mitotic checkpoint protein BubR1 from Cdc20-activated APC (APC(Cdc20)) at the metaphase to anaphase transition. Together, our results suggest that Rae1 and Nup98 are temporal regulators of APC(Cdh1) that maintain euploidy by preventing unscheduled degradation of securin.
Jeganathan
Karthik B
KB
Department of Pediatric and Adolescent Medicine, Mayo College of Medicine, 200 First Street SW, Rochester, Minnesota 55905, USA.
Malureanu
Liviu
L
van Deursen
Jan M
JM
D064173:Anaphase-Promoting Complex-Cyclosome; D000782:Aneuploidy; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D020090:Chromosome Segregation; D005347:Fibroblasts; D006367:HeLa Cells; D006801:Humans; D007621:Karyotyping; D051379:Mice; D008938:Mitosis; D046912:Multiprotein Complexes / Q000378:metabolism; D009630:Nondisjunction, Genetic; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism*; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D064249:Securin; D025801:Ubiquitin / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism
D002352:Carrier Proteins; D046912:Multiprotein Complexes; D034521:Nuclear Matrix-Associated Proteins; D028861:Nuclear Pore Complex Proteins; D029543:Nucleocytoplasmic Transport Proteins; C490521:Rae1 protein, mouse; D064249:Securin; D025801:Ubiquitin; C093350:nuclear pore complex protein 98; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome