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Cdk1 Phosphorylation of the Dam1 Complex Strengthens Kinetochore-Microtubule Attachments.

Authors
  • Gutierrez, Abraham1
  • Kim, Jae Ook2
  • Umbreit, Neil T2
  • Asbury, Charles L3
  • Davis, Trisha N2
  • Miller, Matthew P4
  • Biggins, Sue5
  • 1 Howard Hughes Medical Institute, Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Seattle, WA 98109, USA; Molecular and Cellular Biology Program, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA.
  • 2 Department of Biochemistry, University of Washington, 1705 NE Pacific Street, Seattle, WA 98195, USA.
  • 3 Department of Physiology and Biophysics, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA.
  • 4 Howard Hughes Medical Institute, Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Seattle, WA 98109, USA.
  • 5 Howard Hughes Medical Institute, Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Seattle, WA 98109, USA. Electronic address: [email protected]
Type
Published Article
Journal
Current biology : CB
Publication Date
Nov 16, 2020
Volume
30
Issue
22
Identifiers
DOI: 10.1016/j.cub.2020.08.054
PMID: 32946748
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

To ensure the faithful inheritance of DNA, a macromolecular protein complex called the kinetochore sustains the connection between chromosomes and force-generating dynamic microtubules during cell division. Defects in this process lead to aneuploidy, a common feature of cancer cells and the cause of many developmental diseases [1-4]. One of the major microtubule-binding activities in the kinetochore is mediated by the conserved Ndc80 complex (Ndc80c) [5-7]. In budding yeast, the retention of kinetochores on dynamic microtubule tips also depends on the essential heterodecameric Dam1 complex (Dam1c) [8-15], which binds to the Ndc80c and is proposed to be a functional ortholog of the metazoan Ska complex [16, 17]. The load-bearing activity of the Dam1c depends on its ability to oligomerize, and the purified complex spontaneously self-assembles into microtubule-encircling oligomeric rings, which are proposed to function as collars that allow kinetochores to processively track the plus-end tips of microtubules and harness the forces generated by disassembling microtubules [10-15, 18-22]. However, it is unknown whether there are specific regulatory events that promote Dam1c oligomerization to ensure accurate segregation. Here, we used a reconstitution system to discover that Cdk1, the major mitotic kinase that drives the cell cycle, phosphorylates the Ask1 component of the Dam1c to increase its residence time on microtubules and enhance kinetochore-microtubule attachment strength. We propose that Cdk1 activity promotes Dam1c oligomerization to ensure that kinetochore-microtubule attachments are stabilized as kinetochores come under tension in mitosis. Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

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