Kinetochore protein phosphorylation promotes the correction of erroneous microtubule attachments to ensure faithful chromosome segregation during cell division. Determining how phosphorylation executes error correction requires an understanding of whether kinetochore substrates are completely (i.e., all-or-none) or only fractionally phosphorylated. Using quantitative mass spectrometry (MS), we measured phospho-occupancy on the conserved kinetochore protein Hec1 (NDC80) that directly binds microtubules. None of the positions measured exceeded ∼50% phospho-occupancy, and the cumulative phospho-occupancy changed by only ∼20% in response to changes in microtubule attachment status. The narrow dynamic range of phospho-occupancy is maintained, in part, by the ongoing phosphatase activity. Further, both Cdk1–Cyclin B1 and Aurora kinases phosphorylate Hec1 to enhance error correction in response to different types of microtubule attachment errors. The low inherent phospho-occupancy promotes microtubule attachment to kinetochores while the high sensitivity of kinetochore–microtubule attachments to small changes in phospho-occupancy drives error correction and ensures high mitotic fidelity.
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July 25 2022
Small changes in phospho-occupancy at the kinetochore–microtubule interface drive mitotic fidelity
Thomas J. Kucharski
,
Thomas J. Kucharski
1
Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH
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Rufus Hards,
Rufus Hards
1
Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH
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Sarah E. Vandal
,
Sarah E. Vandal
1
Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH
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Maria Alba Abad
,
Maria Alba Abad
2
Wellcome Centre For Cell Biology, University of Edinburgh, Edinburgh, UK
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A. Arockia Jeyaprakash
,
A. Arockia Jeyaprakash
2
Wellcome Centre For Cell Biology, University of Edinburgh, Edinburgh, UK
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Edward Kaye
,
Edward Kaye
3
Centre for Gene Regulation and Expression, University of Dundee, Dundee, UK
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Aymen al-Rawi
,
Aymen al-Rawi
2
Wellcome Centre For Cell Biology, University of Edinburgh, Edinburgh, UK
3
Centre for Gene Regulation and Expression, University of Dundee, Dundee, UK
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Tony Ly,
Tony Ly
3
Centre for Gene Regulation and Expression, University of Dundee, Dundee, UK
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Kristina M. Godek
,
Kristina M. Godek
1
Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH
4
Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH
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Scott A. Gerber
,
Scott A. Gerber
1
Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH
4
Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH
5
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH
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Duane A. Compton
1
Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH
4
Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH
Correspondence to Duane A. Compton: duane.a.compton@dartmouth.edu
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Thomas J. Kucharski
1
Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH
Rufus Hards
1
Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH
Sarah E. Vandal
1
Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH
Maria Alba Abad
2
Wellcome Centre For Cell Biology, University of Edinburgh, Edinburgh, UK
A. Arockia Jeyaprakash
2
Wellcome Centre For Cell Biology, University of Edinburgh, Edinburgh, UK
Edward Kaye
3
Centre for Gene Regulation and Expression, University of Dundee, Dundee, UK
Aymen al-Rawi
2
Wellcome Centre For Cell Biology, University of Edinburgh, Edinburgh, UK
3
Centre for Gene Regulation and Expression, University of Dundee, Dundee, UK
Tony Ly
3
Centre for Gene Regulation and Expression, University of Dundee, Dundee, UK
Kristina M. Godek
1
Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH
4
Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH
Scott A. Gerber
1
Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH
4
Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH
5
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH
Correspondence to Duane A. Compton: duane.a.compton@dartmouth.edu
Received:
July 17 2021
Revision Received:
April 19 2022
Accepted:
July 05 2022
Online Issn: 1540-8140
Print Issn: 0021-9525
Funding
Funder(s):
Medical Research Council
- Award Id(s): MR/N009738/1
Funder(s):
Fonds de Recherche du Québec—Santé
Funder(s):
Canadian Institutes of Health Research
Funder(s):
National Institutes of Health
- Award Id(s): P20-GM113132
Funder(s):
Dartmouth College
- Award Id(s): GM122846,1R01HD101436,GM051542
Funder(s):
Wellcome Trust
- Award Id(s): 202811
Funder(s):
Royal Society
- Award Id(s): 206211/A/17/Z
Funder(s):
Darwin College, University of Cambridge
- Award Id(s): 218520/Z/19/Z
Funder(s):
Norris Cotton Cancer Center
Funder(s):
National Cancer Institute
- Award Id(s): 5P30 CA023108-40
© 2022 Kucharski et al.
2022
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Cell Biol (2022) 221 (9): e202107107.
Article history
Received:
July 17 2021
Revision Received:
April 19 2022
Accepted:
July 05 2022
Citation
Thomas J. Kucharski, Rufus Hards, Sarah E. Vandal, Maria Alba Abad, A. Arockia Jeyaprakash, Edward Kaye, Aymen al-Rawi, Tony Ly, Kristina M. Godek, Scott A. Gerber, Duane A. Compton; Small changes in phospho-occupancy at the kinetochore–microtubule interface drive mitotic fidelity. J Cell Biol 5 September 2022; 221 (9): e202107107. doi: https://doi.org/10.1083/jcb.202107107
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