Thyroid Hormone Receptor Interacting Protein 13 (TRIP13) AAA-ATPase is a Novel Mitotic Checkpoint Silencing Protein [Signal Transduction]

July 10th, 2014 by Wang, K., Sturt-Gillespie, B., Hittle, J. C., Macdonald, D., Chan, G. K., Yen, T. J., Liu, S.-T.

The mitotic checkpoint (or spindle assembly checkpoint) is a fail-safe mechanism to prevent chromosome missegregation by delaying anaphase onset in the presence of defective kinetochore-microtubule attachment. The target of the checkpoint is the E3 ubiquitin ligase anaphase promoting complex/cyclosome (APC/C). Once all chromosomes are properly attached and bi-oriented at the metaphase plate, the checkpoint needs to be silenced. Previously we and others have reported that TRIP13 AAA-ATPase binds to the mitotic checkpoint silencing protein p31comet. Here we show that endogenous TRIP13 localizes to kinetochores. TRIP13 knockdown delays metaphase-to-anaphase transition. The delay is caused by prolonged presence of the effector for the checkpoint, the mitotic checkpoint complex (MCC) and its association and inhibition of the APC/C. These results suggest that TRIP13 is a novel mitotic checkpoint silencing protein. The ATPase activity of TRIP13 is essential for its checkpoint function, and interference with TRIP13 abolished p31comet mediated mitotic checkpoint silencing. TRIP13 overexpression is a hallmark of cancer cells with chromosomal instability, particularly in certain breast cancers with poor prognosis. We suggest that premature mitotic checkpoint silencing triggered by TRIP13 overexpression may promote cancer development.