such as "Introduction", "Conclusion"..etc
of Washington (UW) researchers are helping to write the operating
manual for the nano-scale machine that separates chromosomes before
cell division. The apparatus is called a spindle because it looks like
a tiny wool-spinner with thin strands of microtubules or spindle fibers
sticking out. The lengthening and shortening of microtubules is thought
to help push and pull apart chromosome pairs.
how this machine accurately and evenly divides genetic material is
essential to learning why its parts sometimes fail. Certain cancers or
birth defects, like Down syndrome or Trisomy 18, result from an uneven
distribution of chromosomes.
In a study published March 6 in the journal Cell,
a team led by UW scientists reports on the workings of a key component
of this machine. Named a kinetochore, it is a site on each chromosome
that mechanically couples to spindle fibers.
also regulatory hubs," the researchers noted. "They control chromosome
movements through the lengthening and shortening of the attached
microtubules. They sense and correct errors in attachment. They emit a
"wait" signal until the microtubules properly attach." Careful control
over microtubules, they added, is vital for accurate splitting of the
The lead researchers on the study were Andrew
F. Powers and Andrew D. Frank from the UW Department of Physiology and
Biophysics and Daniel R. Gestaut, from the UW Department of
Biochemistry. The senior authors of the study were Charles "Chip"
Asbury, assistant professor, and Linda Wordeman, associate professor,
both of physiology and biophysics and both members of the UW Center for
Cell Dynamics; and Trisha Davis, professor of biochemistry, and
director of the Yeast Resource Center.
Asbury is known for
research on molecular machines and motors, Wordeman for work on
chromosome movement, and Davis for studies of spindle poles. All are
part of the Seattle Mitosis Club led by Sue Biggins at the Fred
Hutchinson Cancer Research Center.
To understand how the
kinetochore functions, the scientists sought to uncover the basis for
its most fundamental behavior: attaching microtubules. The most
puzzling aspect of this attachment, according to the researchers, is
that the kinetochore has to be strong yet dynamic. It has to keep a
grip on the microtubule filaments even as they add and remove their
"This ability," the researchers said, "allows the
kinetochore to harness microtubule shortening and lengthening to drive
the movement of chromosomes."
The same coupling behavior is
found in living things from yeast cells to humans, indicating that it
was conserved during evolution as a good way of getting the job done.
question is how this mechanism works. Previous studies implicated a
large, multiprotein complex, Ndc80, as a direct contact point between
kinetochores and microtubules. However, researchers had only a static
view of the complex. The UW researchers used special techniques to
manipulate and track the activity of the complex in a laboratory set-up.
researchers were able to show that the Ndc80 complex was indeed capable
of forming dynamic, load-bearing attachments to the tips of the
microtubules, probably by forming an array of individually weak
microtubule binding elements that rapidly bind and unbind, but with a
total energy large enough to hold on. The mechanism will produce a
molecular friction that resists translocation of the microtubule
through the attachment site. Other scientists have dubbed the mechanism
a "slip clutch."
This kind of coupler, the researchers added,
is able to remain continuously attached to the microtubule tip during
both its assembly and disassembly phases. The coupler also can harness
the energy released during disassembly to produce mechanical force.
Coupling may depend on positively charged areas on the complex that
interact with negatively charged hooks on the microtubules by
Based on their findings, the scientists
propose arrays of Ndc80 complexes supply the combination of plasticity
and strength that allows kinetechores to hold on loosely but not let go
of the tips of the microtubules.
University of Washington
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