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Cited by 453Microtubule and mitosis dynamicsDNA Repair MechanismsGenomics and Chromatin Dynamics

Genome stability is ensured by temporal control of kinetochore–microtubule dynamics

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Bakhoum, Samuel F., Thompson, Sarah L., Manning, Amity L., Compton, Duane A.·2009·Nature Cell Biology
DOI 10.1038/ncb1809PMC PMC2614462
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Abstract

Most solid tumours are aneuploid and many frequently mis-segregate chromosomes. This chromosomal instability is commonly caused by persistent mal-oriented attachment of chromosomes to spindle microtubules. Chromosome segregation requires stable microtubule attachment at kinetochores, yet those attachments must be sufficiently dynamic to permit correction of mal-orientations. How this balance is achieved is unknown, and the permissible boundaries of attachment stability versus dynamics essential for genome stability remain poorly understood. Here we show that two microtubule-depolymerizing kinesins, Kif2b and MCAK, stimulate kinetochore-microtubule dynamics during distinct phases of mitosis to correct mal-orientations. Few-fold reductions in kinetochore-microtubule turnover, particularly in early mitosis, induce severe chromosome segregation defects. In addition, we show that stimulation of microtubule dynamics at kinetochores restores stability to chromosomally unstable tumour cell lines, establishing a causal relationship between deregulation of kinetochore-microtubule dynamics and chromosomal instability. Thus, temporal control of microtubule attachment to chromosomes during mitosis is central to genome stability in human cells.

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  • Overexpression of Kif2b or MCAK directly suppresses CIN in otherwise chromosomally unstable cells.

    “Destabilization of microtubule attachments to chromosomes at the kinetochores, through overexpression of the non-motile microtubule depolymerizing kinesin-13 proteins, Kif2b or MCAK/Kif2c, directly suppresses CIN in otherwise chromosomally unstable cells5–7.”

    From Chromosomal instability drives metastasis through a cytosolic DNA response (2018) · cites this paper as [7]

  • Cells overexpressing Kif2b or MCAK continue to propagate abnormal aneuploid karyotypes in a stable manner.

    “Cells overexpressing Kif2b or MCAK continue to propagate abnormal aneuploid karyotypes albeit in a stable manner7.”

    From Chromosomal instability drives metastasis through a cytosolic DNA response (2018) · cites this paper as [7]

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Cited by

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Authors
Bakhoum, S. F., Thompson, S. L., Manning, A. L., & Compton, D. A.
Affiliations
Dartmouth College (US)
Corresponding author
Compton, Duane A.
ORCID
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2008-12-07
Volume
11
Issue
1
Pages
27-35
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
DOI
10.1038/ncb1809
PMC
PMC2614462
OpenAlex
W2076814468
Cited by
453
References
2
Citations by year
2026: 7 · 2025: 16 · 2024: 25 · 2023: 29 · 2022: 36 · 2021: 40 · 2020: 28 · 2019: 19 · 2018: 20 · 2017: 29 · 2016: 29 · 2015: 22 · 2014: 29 · 2013: 18 · 2012: 27
FWCI
11.53
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (P30CA023108)
  • National Institute of General Medical Sciences (GM51542, R01GM051542, T32GM008704, R37GM051542, GM008704)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
kinetochore-microtubule attachment, microtubule dynamics, chromosomal instability, genome stability, chromosome segregation, MCAK, kinesin, microtubule depolymerization, mitosis, aneuploidy, cancer cells, spindle assembly
MeSH terms
Aneuploidy, Cell Transformation, Neoplastic, Chromosome Aberrations, Humans, Microtubules, Mitosis, Spindle Apparatus, Recombinant Fusion Proteins, Tubulin, Kinesins, Kinetochores, Chromosome Segregation, Genomic Instability, Cell Line, Tumor, Green Fluorescent Proteins

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