Abstract
The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20. When the checkpoint signal is turned off, MCC is disassembled and the checkpoint is inactivated. The mechanisms of the disassembly of MCC are not sufficiently understood. We have previously observed that ATP hydrolysis is required for the action of the Mad2-binding protein p31(comet) to disassemble MCC. We now show that HeLa cell extracts contain a factor that promotes ATP- and p31(comet)-dependent disassembly of a Cdc20-Mad2 subcomplex and identify it as Thyroid Receptor Interacting Protein 13 (TRIP13), an AAA-ATPase known to interact with p31(comet). The joint action of TRIP13 and p31(comet) also promotes the release of Mad2 from MCC, participates in the complete disassembly of MCC and abrogates checkpoint inhibition of APC/C. We propose that TRIP13 plays centrally important roles in the sequence of events leading to MCC disassembly and checkpoint inactivation.
Highlights
The mitotic checkpoint is a surveillance system that prevents premature separation of sister chromatids in mitosis and ensures the fidelity of chromosome segregation
We found that the joint action of Thyroid Receptor Interacting Protein 13 (TRIP13) and p31comet promotes Mitotic Checkpoint Complex (MCC) disassembly, releases AnaphasePromoting Complex/Cyclosome (APC/C) from checkpoint inhibition, and inactivates the mitotic checkpoint
We have previously reported that a Cdc20–Mad2 subcomplex is an intermediary product in the disassembly of MCC [10]
Summary
The mitotic (or spindle assembly) checkpoint is a surveillance system that prevents premature separation of sister chromatids in mitosis and ensures the fidelity of chromosome segregation. It monitors the existence of chromatids that are not attached yet correctly to the mitotic spindle through their kinetochores and delays anaphase until correct bipolar attachment is achieved It acts by inhibiting the Anaphase Promoting Complex/Cyclosome (APC/C), a ubiquitin ligase that targets for degradation cyclin B and securin, an inhibitor of anaphase initiation. We found that the joint action of TRIP13 and p31comet promotes MCC disassembly, releases APC/C from checkpoint inhibition, and inactivates the mitotic checkpoint. The mitotic checkpoint system has an important role to ensure accurate segregation of chromosomes in mitosis This system regulates the activity of the ubiquitin ligase AnaphasePromoting Complex/Cyclosome (APC/C) by the formation of a negatively acting Mitotic Checkpoint Complex (MCC). The results reveal an important molecular mechanism in the regulation of APC/C by the mitotic checkpoint
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