Molecular forces are key to proper cell division
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| Thomas Maresca, UMass Amherst |
Studies led by cell biologist Thomas Maresca at the University
of Massachusetts Amherst are revealing new details about a molecular
surveillance system that helps detect and correct errors in cell division that
can lead to cell death or human diseases. Findings are reported in the current
issue of the Journal of
Cell Biology. The purpose of cell division is to evenly distribute the
genome between two daughter cells. To achieve this, every chromosome must
properly interact with a football-shaped structure called the spindle. However,
interaction errors between the chromosomes and spindle during division are
amazingly common, occurring in 86 to 90 percent of chromosomes, says Maresca,
an expert in mitosis.
"This is not quite so surprising when you realize that
every single one of the 46 chromosomes has to get into perfect position every
time a cell divides," he notes. The key to flawless cell division is to
correct dangerous interactions before the cell splits in two.
Working with fruit fly tissue culture cells, Maresca and
graduate students Stuart Cane and Anna Ye have developed a way to watch and
record images of the key players in cell division including microtubule
filaments that form the mitotic spindle and sites called kinetochores that
mediate chromosome-microtubule interactions. They also examined the
contribution of a force generated by molecular engines called the polar
ejection force (PEF), which is thought to help line up the chromosomes in the
middle of the spindle for division. For the first time, they directly tested
and quantified how PEF, in particular, influences tension at kinetochores and
affects error correction in mitosis.
"We also now have a powerful new assay to get at how this
tension regulates kinetochore-microtubule interactions," Maresca adds.
"We knew forces and tension regulated this process, but we didn't
understand exactly how. With the new technique, we can start to dissect out how
tension modulates error correction to repair the many erroneous attachment
intermediates that form during division."
The cell biologists conduct their experiments inside living
cells. In normal cell division, chromosomes line up in the center, where two
copies of each chromosome are held together with "molecular glue"
until signaled to dissolve the glue and divide. To oversimplify, each
chromosome copy is then pulled to opposite poles of the cell, escorted in what
looks like a taffy pull away from the center as two new daughter cells are
formed.
During the split, molecular engines pull the copies apart along
microtubule tracks that take an active role in the process that includes
shortening microtubules by large, flexible scaffold-like protein structures
called kinetochores that assemble on every chromosome during division. Maresca
and colleagues say until this study revealed details, PEF's function as a
kinetochore regulator has been underappreciated.
Overall, this well-orchestrated process prevents serious
problems such as aneuploidy, that is, too many chromosomes in daughter cells.
Aneuploidy in somatic or body cells leads to cell death and is a hallmark of
most cancer cells. But in eggs or sperm, it leads to serious birth defects and
miscarriages.
In properly aligned division, microtubules from opposite spindle
poles tug chromosome copies toward opposite poles, but they stick together with
molecular glue until the proper moment. This creates tension at the
kinetochores and stabilizes their interactions with microtubules. However, if
attachments are bad, or syntelic, both copies attach to the same pole, leading
to chromosome mis-segregation and aneuploidy if uncorrected. "Cells have a
surveillance mechanism that allows them to wait for every chromosome to
properly align before divvying up the chromosomes," Maresca says.
"It's clear in our movies that the cell waits for the last kinetochores to
correctly orient before moving forward."
To study this at the molecular level, Maresca and colleagues
designed experiments to trick the cellular machinery into overexpressing the
molecular engine that produces PEF. Surprisingly, this caused a dramatic
increase in a type of bad kinetochore-microtubule interaction called syntelic
attachments. They also fluorescently tag chromosomes, microtubules,
kinetochores and the molecular engine kinesin with different colors to visualize
interactions in real time using a special microscope at UMass Amherst able to
image single molecules. Quantifying the amount of fluorescence of the
force-producing molecular engine, they were able to assess the relative
strength of the PEF in cells.
Maresca says, "We see the detection pathway preventing the
molecular glue from dissolving until every chromosome is correctly aligned. The
delay gives the cell time to correct errors. We propose that these bad syntelic
attachments are normally very short-lived because they are not under proper
tension. However, when we experimentally elevate PEF, tension is introduced at
attachments that do not typically come under tension, essentially tricking the
cell into thinking these chromosomes are properly aligned."
Plotting the percent of syntelic attachments versus the amount
of PEF, Maresca and colleagues observed an error rate that plateaus at 80 to 90
percent, mirroring and supporting earlier work by others in different cell
types. "In cells with elevated PEFs, the correction pathway is overridden,
the detection mechanism is silenced and the result is disastrous because it
leads to severe aneuploidy. This research has taught us about how an important
molecular engine generates the PEF and how this force affects the accuracy of
cell division."
Source: University of Massachusetts
Amherst
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