Yeast Fin1-PP1 dephosphorylates an Ipl1 substrate, Ndc80, to remove Bub1-Bub3 checkpoint proteins from the kinetochore during anaphase.

Michael Bokros,Yanchang Wang,Delaney Sherwin,Marie-Helene Kabbaj,Gregory P Copenhaver

doi:10.1371/journal.pgen.1009592

Abstract

The spindle assembly checkpoint (SAC) prevents anaphase onset in response to chromosome attachment defects, and SAC silencing is essential for anaphase onset. Following anaphase onset, activated Cdc14 phosphatase dephosphorylates the substrates of cyclin-dependent kinase to facilitate anaphase progression and mitotic exit. In budding yeast, Cdc14 dephosphorylates Fin1, a regulatory subunit of protein phosphatase 1 (PP1), to enable kinetochore localization of Fin1-PP1. We previously showed that kinetochore-localized Fin1-PP1 promotes the removal of the SAC protein Bub1 from the kinetochore during anaphase. We report here that Fin1-PP1 also promotes kinetochore removal of Bub3, the Bub1 partner, but has no effect on another SAC protein Mad1. Moreover, the kinetochore localization of Bub1-Bub3 during anaphase requires Aurora B/Ipl1 kinase activity. We further showed that Fin1-PP1 facilitates the dephosphorylation of kinetochore protein Ndc80, a known Ipl1 substrate. This dephosphorylation reduces kinetochore association of Bub1-Bub3 during anaphase. In addition, we found that untimely Ndc80 dephosphorylation causes viability loss in response to tensionless chromosome attachments. These results suggest that timely localization of Fin1-PP1 to the kinetochore controls the functional window of SAC and is therefore critical for faithful chromosome segregation.

Highlights

During cell division, chromosomes are segregated into daughter cells, and faithful chromosome segregation is essential to maintain the genome integrity of all living organisms
Mistakes in chromosome attachment activate the spindle assembly checkpoint to stop the cell cycle for error correction. This activation depends on kinetochore recruitment of checkpoint proteins, including the Bub1-Bub3 complex
After cells have established chromosome bipolar attachment, the spindle assembly checkpoint is silenced by protein phosphatase 1 (PP1) to enable anaphase entry

Summary

Introduction

Chromosomes are segregated into daughter cells, and faithful chromosome segregation is essential to maintain the genome integrity of all living organisms. The failure of this process results in aneuploidy, a hallmark of cancers and genetic diseases like Trisomy 21 [1,2]. Incorrect attachments between the kinetochore and the spindle microtubules activate the spindle assembly checkpoint (SAC) to prevent anaphase onset. The SAC activation depends on the recruitment of SAC proteins to kinetochores [3]. Bub further recruits SAC proteins Mad and Mad for SAC activation [4,5,6]

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Conclusion