Kinase activity of fission yeast Mph1 Is required for Mad2 and Mad3 to stably bind the anaphase promoting complex

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Abstract

Defects in chromosome segregation result in aneuploidy, which can lead to disease or cell death [1, 2]. The spindle checkpoint delays anaphase onset until all chromosomes are attached to spindle microtubules in a bipolar fashion [3, 4]. Mad2 is a key checkpoint component that undergoes conformational activation, catalyzed by a Mad1-Mad2 template enriched at unattached kinetochores [5]. Mad2 and Mad3 (BubR1) then bind and inhibit Cdc20 to form the mitotic checkpoint complex (MCC), which binds and inhibits the anaphase promoting complex (APC/C). Checkpoint kinases (Aurora, Bub1, and Mps1) are critical for checkpoint signaling, yet they have poorly defined roles and few substrates have been identified [6-8]. Here we demonstrate that a kinase-dead allele of the fission yeast MPS1 homolog (Mph1) is checkpoint defective and that levels of APC/C-associated Mad2 and Mad3 are dramatically reduced in this mutant. Thus, MCC binding to fission yeast APC/C is dependent on Mph1 kinase activity. We map and mutate several phosphorylation sites in Mad2, producing mutants that display reduced Cdc20-APC/C binding and an inability to maintain checkpoint arrest. We conclude that Mph1 kinase regulates the association of Mad2 with its binding partners and thereby mitotic arrest. © 2012 Elsevier Ltd. All rights reserved.

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Zich, J., Sochaj, A. M., Syred, H. M., Milne, L., Cook, A. G., Ohkura, H., … Hardwick, K. G. (2012). Kinase activity of fission yeast Mph1 Is required for Mad2 and Mad3 to stably bind the anaphase promoting complex. Current Biology, 22(4), 296–301. https://doi.org/10.1016/j.cub.2011.12.049

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