TRIP13 and APC15 drive mitotic exit by turnover of interphase- and unattached kinetochore-produced MCC.

The mitotic checkpoint ensures accurate chromosome segregation through assembly of the mitotic checkpoint complex (MCC), a soluble inhibitor of the anaphase-promoting complex/cyclosome (APC/C) produced by unattached kinetochores. MCC is also assembled during interphase by Mad1/Mad2 bound at nuclear pores, thereby preventing premature mitotic exit prior to kinetochore maturation and checkpoint activation. Using degron tagging to rapidly deplete the AAA+ ATPase TRIP13, we show that its catalytic activity is required to maintain a pool of open-state Mad2 for MCC assembly, thereby supporting mitotic checkpoint activation, but is also required for timely mitotic exit through catalytic disassembly of MCC. Strikingly, combining TRIP13 depletion with elimination of APC15-dependent Cdc20 ubiquitination/degradation results in a complete inability to exit mitosis, even when MCC assembly at unattached kinetochores is prevented. Thus, mitotic exit requires MCC produced either in interphase or mitosis to be disassembled by TRIP13-catalyzed removal of Mad2 or APC15-driven ubiquitination/degradation of its Cdc20 subunit. The mitotic checkpoint complex (MCC) is assembled during both mitosis and interphase. Here, the authors use auxin-inducible degron tags to rapidly degrade TRIP13 and find that mitotic exit requires MCC disassembly by TRIP13-catalyzed removal of Mad2 or APC1-driven ubiquitination of Cdc20.

有丝分裂检查点通过有丝分裂检查点复合物（MCC）的组装确保染色体准确分离，MCC是由未连接的动粒产生的后期促进复合物/周期体（APC/C）的一种可溶性抑制剂。在间期，MCC也由结合在核孔的Mad1/Mad2组装而成，从而在动粒成熟和检查点激活之前防止过早的有丝分裂退出。通过使用降解决定子标签快速耗尽AAA + ATP酶TRIP13，我们表明其催化活性是维持用于MCC组装的开放状态Mad2库所必需的，从而支持有丝分裂检查点的激活，但对于通过MCC的催化分解及时退出有丝分裂也是必需的。令人惊讶的是，将TRIP13的耗尽与消除APC15依赖的Cdc20泛素化/降解相结合，会导致完全无法退出有丝分裂，即使在未连接的动粒处的MCC组装被阻止时也是如此。因此，有丝分裂退出需要在间期或有丝分裂中产生的MCC通过TRIP13催化去除Mad2或APC15驱动的其Cdc20亚基的泛素化/降解来分解。 有丝分裂检查点复合物（MCC）在有丝分裂和间期都会组装。在这里，作者使用生长素诱导的降解决定子标签快速降解TRIP13，并发现有丝分裂退出需要通过TRIP13催化去除Mad2或APC1驱动的Cdc20泛素化来分解MCC。