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PMID: 19060894 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Genome stability is ensured by temporal control of kinetochore-microtubule dynamics.

Nature cell biology ·Vol. 11 ·No. 1 ·2009-01-00 ·Pages 27-35

Bakhoum SF, Thompson SL, Manning AL, Compton DA

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.

MeSH Terms
Aneuploidy Cell Line, Tumor Cell Transformation, Neoplastic/genetics Chromosome Aberrations Chromosome Segregation/physiology Genomic Instability/physiology Green Fluorescent Proteins/genetics,metabolism Humans Kinesins/metabolism Kinetochores/physiology,ultrastructure Microtubules/physiology,ultrastructure Mitosis/physiology Recombinant Fusion Proteins/genetics,metabolism Spindle Apparatus/physiology,ultrastructure Tubulin/genetics,metabolism
Chemicals
KIF2C protein, human Recombinant Fusion Proteins Tubulin Green Fluorescent Proteins KIF2B protein, human Kinesins
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Bakhoum Samuel F
Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755, USA.
Thompson Sarah L
Manning Amity L
Compton Duane A
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Article Info
Journal
Nature cell biology
Abbr.
Nat Cell Biol
ISSN
1476-4679
DOI
10.1038/ncb1809
Published
2009-01-00
Epub
2008-00-07
Pages
27-35
Language
English
Region
England
NLM ID
100890575
PMCID
PMC2614462
Subset
IM
Grants
NCI NIH HHS · P30 CA023108 · United States
NIGMS NIH HHS · GM008704 · United States
NIGMS NIH HHS · R01 GM051542-12 · United States
NIGMS NIH HHS · GM51542 · United States
NIGMS NIH HHS · R37 GM051542 · United States
NIGMS NIH HHS · R01 GM051542 · United States
NIGMS NIH HHS · T32 GM008704 · United States
External Links
PubMed source DOI: 10.1038/ncb1809 PMC Full Text View journal details
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