December 28, 2007 | David F. Coppedge

Quality Control Ensures Accurate Cell Division

Cell division (mitosis) is a very complex process in which every part must be accurately duplicated and sent to the proper destination.  Picture a marching band where each flute player or tuba player is able to clone itself.  The players congregate at the center in two lines, divide, and move apart, forming two marching bands that can each play independently or as part of a parade of bands.  A more realistic picture might require imagining the whole school – library, shop, offices and all – splitting into two identical copies in a matter of hours or minutes.
    How does the cell make sure that each copy is identical?  Accurate copying is essential, or else errors would accumulate and bring the species to an end.  Scientists continue to uncover some of the quality-control policies and procedural tricks that cells follow.

  1. A nine in time saves stitch:  Centrosomes control the orientation of chromosomes before the split.  They create a spindle of microtubules that line the pairs up at the midplane, then pull them apart.  Within the centrosomes are two motors called centrioles, oriented perpendicular to one another, that look for all the world like turbines.  The blades of the turbine are microtubules with spokes, forming a cylinder that looks like a pie with exactly nine slices.  Why nine, and only nine?
        Wallace Marshall (UC San Francisco) reviewed experiments into the mechanical basis for nine-ness in centrioles, and published a report in Current Biology.1  Experiments with mutants show that the number is controlled by the length of the spokes that emanate from each slice.  This sets the overall diameter of the centriole, and thus the number of pie slices that will fit in the cylinder.
        “This study provides an interesting geometrical mechanism by which a length can control a number,” Marshall said.  Why was the research worthwhile?  “Understanding centriole assembly is likely to reveal many more engineering-design principles that cells use to build complex structures.
  2. Herding the chromosomes:  When a chromosome pair lines up on the spindle midplane right before splitting up, it contains a structure at the waistband called a centromere.  This belt of protein contains two attachment points, called kinetochores, used by microtubules to pull them into their respective daughter cells.  Our 03/04/2004 entry used the analogy of cowboys lassoing pairs of cattle and pulling them into separate corrals.  The yoke holding each pair of cows together is the centromere, and the kinetochores are like saddle horns the ropes can latch onto.  Opposing cowboys lasso the horns and start pulling in opposite directions.  When all pairs are lined up and accounted for, a foreman named aurora B kinase breaks the yokes, and the cowboys haul in their herds.
        The geometry of the centromere is essential for keeping this process error-free, a team from New York and Moscow reported in Nature last month.2  Once in awhile, two cowboys on the same side lasso the same pair (this is called syntelic attachment).  Unless corrected, one cell would get both chromosomes and the other would get neither; this “non-disjunction” fault could lead to genetic disorders or cancer.  Scientists had previously thought that detaching one rope (microtubule) would make the saddle horn (kinetochore) automatically spring back into position for a rope from the other side.  It’s apparently not as simple as that.  More quality-control mechanisms are involved.  “Achieving chromosome bi-orientation depends on a complex interplay between mechanisms intrinsic to the centromere and those that act externally,” they said.  After cross-attachment fibers are released, and after the lassos are disconnected, there are intrinsic properties of the centromere that come into play.  “Our findings imply that mechanical properties and the shape of the centromere play an important part in the fidelity of chromosome segregation.”  Unless everything works, the operation usually aborts.  Security engineers might call this an example of the principle of defense in depth.
  3. Pinch me:  Perhaps you’ve watched movies of dividing cells, and noticed how they pinch off from each other, as if someone tied a string around a soft balloon and pulled it tight.  Since no person is around at the cell level to do this task manually, there must be an automatic molecular mechanism that makes it work.  What forms the “contractile ring” and reels it in?
        An article in Science Daily described work by scientists from Yale, Columbia and Lehigh to figure out what happens.  Cells employ the same molecular motors, actin and myosin, that make muscles work.  Actin filaments with attached myosin motors assemble along the inner cell membrane at the dividing plane, and go through a “search, capture, pull and release” operation.  Being blind, molecules “feel” their way to neighboring molecules by putting out filaments in random directions.  A myosin motor on the neighbor captures the actin filament and pulls on it.  Surprisingly, it lets go after about 20 seconds.  Why?  “The assembly involves many episodes of attractions between pairs of nodes proceeding in parallel,” the article explains.  “Eventually the nodes form into a condensed contractile ring around the equator, ready to pinch the mother into two daughters at a later stage.”
        The repeating rounds of “release and capture” appear essential to the assembly process of the contractile ring, they said.  Like pulling on a purse string, the circle tightens till the cells are pinched off and go their separate ways.
        The scientists figured this out by comparing models with observations in an iterative fashion.  The work was done on “simple” yeast cells.  “Future work will involve testing the concepts learned from fission yeast in other cells to learn if the mechanism is universal,” said Thomas Pollard [Yale].  “Since other cells, including human cells, depend on similar proteins for cytokinesis, it is entirely possible that they use the same strategy.”  An abstract of the work appears on Science Express in advance of publication.  The following week it was published in Science.3
  4. Plant protection and bearing walls:  Dividing plant cells have a different problem.  They have cell walls.  What determines the exact point at where the wall between two newly-divided cells will form?  Shrink yourself down to the size of a plant cell in your imagination, and you can see the difficulty.  If you were the foreman of a group of construction workers making a house divide in two, how do you remember where the new wall between them is supposed to go?
        Clive Lloyd and Henrik Buschmann (Department of Cell and Developmental Biology, John Innes Centre, Norwich UK) wrote about this predicament in Current Biology.4  What was mysterious is that a structure of microtubules known to form at the dividing plane apparently disassembles right before cell division.  How does the cell “memorize” the position of the plane where the future cell wall will form?  The trick is somewhat like using a chalk line.  The microtubules attract special proteins that adhere to the exact spot, forming a ring around the perimeter.  The microtubule scaffolding, no longer needed, is then dismantled.  After the chromosomes migrate and cell division completes, a plate of cell-wall proteins grows outward toward the chalk ring.  If you can imagine wallboard that grows into position from the center of the room, attracted to the chalk line, you get the idea.  The result is a neat, flat, parallel wall, subdividing the daughter cells into their own rooms.
        Without these memory proteins, the scientists found, cell walls grew at abnormal positions.  Stay tuned, because this doesn’t explain everything about how plants determine the division plane.  It’s just an intriguing start.  “The search now continues for other components of the division ring and insights into the attractive influence they exert over the leading edge of the cytokinetic apparatus,” they said.

One other recent cell biology paper, not directly about mitosis, is worthy of note.  All proteins in the cell need to fold properly before going into service.  Many of them use a “dressing room” called GroEL-GroES to avoid the hustle and bustle of the cytoplasm (05/05/2003, 06/07/2006).  A team of biochemists from Yale, Howard Hughes, U of Pennsylvania and Scripps, publishing in PNAS,5 asked why one particular protein really needs the dressing room when it can fold outside.
    During the folding process, the amino acid chain seeks its “native” or correct fold.  If it works the first time or two, all is well; if it cannot fold in time, the chain can degenerate into a glob or “aggregate” that is either useless or dangerous and must be destroyed.  The team found that the GroEL “chaperone” is more likely to prevent aggregation if the chain goes down the wrong folding pathway.  In the safe, barrel-shaped chamber of the chaperone, the chain can more easily unfold and try again.  Outside, bad folds are less likely to get another chance.

1.  Wallace F. Marshall, “Centriole Assembly: The Origin of Nine-ness,” Current Biology, Volume 17, Issue 24, 18 December 2007, Pages R1057-R1059.
2.  Loncaronarek et al, “The centromere geometry essential for keeping mitosis error free is controlled by spindle forces,” Nature 450, 745-749 (29 November 2007) | doi:10.1038/nature06344.
3.  Vavylonis et al, “Assembly Mechanism of the Contractile Ring for Cytokinesis by Fission Yeast,” Science, 4 January 2008: Vol. 319. no. 5859, pp. 97-100, DOI: 10.1126/science.1151086.
4.  Clive Lloyd and Henrik Buschmann, “Plant Division: Remembering Where to Build the Wall,” Current Biology, Volume 17, Issue 24, 18 December 2007, Pages R1053-R1055.
5.  Horst, Fenton, Englander, Wuthrich and Horwich, “Folding trajectories of human dihydrofolate reductase inside the GroEL-GroES chaperonin cavity and free in solution,” Proceedings of the National Academy of Sciences USA, published online before print December 19, 2007, 10.1073/pnas.0710042105.

The views of cells you got in high school through a light microscope are about as useful for understanding what really goes on as trying to fathom a city from an airplane.  Only now, in our time, are the techniques improving to the point where we can enter the factories and offices at ground level to really begin to understand.
    Our great joy and mission at Creation-Evolution Headlines is to bring these fascinating discoveries, hidden away in abstruse journals, to the public in a timely, understandable way, so that readers can wonder at the amazing design so clearly apparent at the tiniest basis of life – the cell – and realize how utterly bankrupt is the theory of evolution to explain them.
    As is almost always the case, none of these papers dared to speculate about how these incredible mechanisms might have evolved by a blind, purposeless process of chance.  Darwin’s theory was written for a past era when the cell seemed as simple as a blob of jello.  Wave him and his theory good-bye as we fast-forward into the 21st century era of molecular machinery.  Biology of the future is reserved for those who appreciate and understand “engineering-design principles.”

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