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Mps1 regulates kinetochore-microtubule attachment stability via the ska complex to ensure error-free chromosome segregation

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Maciejowski, John, Drechsler, Hauke, Grundner-Culemann, Kathrin, Ballister, Edward R., Rodriguez-Rodriguez, Jose-Antonio, Rodriguez-Bravo, Veronica, Jones, Mathew J. K., Foley, Emily, Lampson, Michael A., Daub, Henrik, McAinsh, Andrew D. and Jallepalli, Prasad V. (2017) Mps1 regulates kinetochore-microtubule attachment stability via the ska complex to ensure error-free chromosome segregation. Developmental Cell, 41 (2). 143-156.e6. doi:10.1016/j.devcel.2017.03.025 ISSN 1534-5807.

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Official URL: http://dx.doi.org/10.1016/j.devcel.2017.03.025

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Abstract

The spindle assembly checkpoint kinase Mps1 not only inhibits anaphase but also corrects erroneous attachments that could lead to missegregation and aneuploidy. However, Mps1’s error correction-relevant substrates are unknown. Using a chemically tuned kinetochore-targeting assay, we show that Mps1 destabilizes microtubule attachments (K fibers) epistatically to Aurora B, the other major error-correcting kinase. Through quantitative proteomics, we identify multiple sites of Mps1-regulated phosphorylation at the outer kinetochore. Substrate modification was microtubule sensitive and opposed by PP2A-B56 phosphatases that stabilize chromosome-spindle attachment. Consistently, Mps1 inhibition rescued K-fiber stability after depleting PP2A-B56. We also identify the Ska complex as a key effector of Mps1 at the kinetochore-microtubule interface, as mutations that mimic constitutive phosphorylation destabilized K fibers in vivo and reduced the efficiency of the Ska complex’s conversion from lattice diffusion to end-coupled microtubule binding in vitro. Our results reveal how Mps1 dynamically modifies kinetochores to correct improper attachments and ensure faithful chromosome segregation.

Item Type: Journal Article
Divisions: Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Journal or Publication Title: Developmental Cell
Publisher: Cell Press
ISSN: 1534-5807
Official Date: 24 April 2017
Dates:
DateEvent
24 April 2017Published
30 March 2017Accepted
Volume: 41
Number: 2
Page Range: 143-156.e6
DOI: 10.1016/j.devcel.2017.03.025
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access
Date of first compliant deposit: 9 August 2017
Date of first compliant Open Access: 15 June 2018
Open Access Version:
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