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Microtubule tethers at kinetochores and spindle poles : essential mitotic components

  • Author(s): Silk, Alain Daniel
  • et al.
Abstract

Mitosis is the period of the cell cycle during which the duplicated genome is equally partitioned into two daughter cells. This is accomplished by the alignment of paired sister chromatids in metaphase and the accurate segregation of sisters in anaphase. The faithful alignment and segregation of chromosomes relies on the assembly of cytoskeletal elements into the bipolar mitotic spindle, the productive attachment of spindle fibers to kinetochores on each chromosome, and the focusing and anchoring of microtubule bundles at spindle poles. Errors in these various aspects of mitosis have severe consequences with regards to embryonic development, cellular viability, and tumorigenesis. Disruption of kinetochore function leading to reduced microtubule attachment and decreased checkpoint signaling results in the gain or loss of whole chromosomes (aneuploidy), which is a hallmark of cancer. However, whether aneuploidy is a cause or effect of tumorigenesis has remained untested since it was first suggested as an agent of carcinogenesis more than 100 years ago. Heterozygosity for the microtubule-binding, kinetochore localized, kinesin-like motor protein, CENP-E, results in the development of aneuploidy in cultured cells and in vivo in the absence of additional genomic instability. A variety of studies presented here, using CENP-E heterozygous animals, demonstrate that elevated rates of chromosome segregation errors act in a context dependent manner to either promote or inhibit tumorigenesis. At the opposite end of spindle microtubules, the poles, the requirement for microtubule associated cross-linking proteins in establishing and maintaining normal spindle structure has remained unclear. Construction and analysis of a conditional, loss-of- mitotic-function allele of the microtubule binding, coiled -coil protein NuMA, in mice and in cultured primary cells demonstrates that NuMA is an essential mitotic component. NuMA makes distinct contributions to the establishment and maintenance of focused spindle poles. When NuMA function is disrupted, centrosomes provide initial focusing activity, but continued centrosome attachment to bi-polar spindles under tension, and maintenance of focused kinetochore-fibers at spindle poles require NuMA's microtubule binding capacity. Without centrosomes and NuMA function, spindle microtubule focusing completely fails to become established. Thus, microtubule-tethers at kinetochores and spindle poles are essential components for normal progression through mitosis

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