Kinase Activity of Fission Yeast Mph1 Is Required for Mad2 and Mad3 to Stably Bind the Anaphase Promoting Complex

Judith Zich, Alicja M Sochaj, Heather M Syred, Laura Milne, Atlanta G Cook, Hiro Ohkura, Juri Rappsilber, Kevin G Hardwick

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)296–301
JournalCurrent Biology
Volume22
Issue number4
DOIs
Publication statusPublished - 21 Feb 2012

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