Genome stability is ensured by temporal control of kinetochore-microtubule dynamics.
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.
Bakhoum
Samuel F
SF
Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755, USA.
Thompson
Sarah L
SL
Manning
Amity L
AL
Compton
Duane A
DA
D000782:Aneuploidy; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002869:Chromosome Aberrations; D020090:Chromosome Segregation / Q000502:physiology*; D042822:Genomic Instability / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D018386:Kinetochores / Q000502:physiology* / Q000648:ultrastructure; D008870:Microtubules / Q000502:physiology* / Q000648:ultrastructure; D008938:Mitosis / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D008941:Spindle Apparatus / Q000502:physiology* / Q000648:ultrastructure; D014404:Tubulin / Q000235:genetics / Q000378:metabolism
C091489:KIF2C protein, human; D011993:Recombinant Fusion Proteins; D014404:Tubulin; D049452:Green Fluorescent Proteins; C523507:KIF2B protein, human; D016547:Kinesins