Securin associates with APC^Cdh1 in prometaphase but its destruction is delayed by Rae1 and Nup98 until the metaphase/anaphase transition

Precisely timed ubiquitin-mediated proteolysis of mitotic regulators by the anaphase-promoting complex (APC) governs the orderly passage of cells through mitosis. The established view is that Cdc20-activated APC (APC^Cdc20) mediates the destruction of cyclin B and securin at the metaphase/anaphase transition, and that Cdh1-activated APC (APC^Cdh1) has no role in this process. We recently reported that securin, but not cyclin B, is prematurely targeted for destruction by the APC in mutant mice that have low levels of the nuclear transport factors Rae1 and Nup98. We found that Rae1 and Nup98 assemble into a complex with APC^Cdh1 in prometaphase and act to delay APC ^Cdh1-mediated ubiquitination of securin until the metaphase/anaphase transition. Here we show that Rae1 and Nup98 not only form a complex with APC^Cdh1 in prometaphase but also with securin. This finding suggests that the Rae1-Nup98 complex does not inhibit early destruction of securin by preventing APC^Cdh1 from binding to securin, but by preventing ubiquitination of APC^Cdh1-bound securin. We propose that the formation of APC^Cdh1-securin complexes in prometaphase primes the cell for rapid securin degradation after release of the inhibitory Rae1-Nup98 complex at the metaphase/anaphase transition. We further report here that mutant mice with low levels of the Rae1-Nup98 complex are not prone to develop spontaneous tumors, despite massive aneuploidy. However, Rae1/Nup98 mutant mice are significantly more susceptible to DMBA-induced lung tumors than wild-type mice, indicating that combined Rae1/ Nup98 haplo-insufficiency does promote tumorigenesis when certain cancer-critical genes are also mutated.