Cellular Cowboys: How the Cell Rounds Up Chromosomes Before Dividing

Two cancer researchers from UC San Diego describe mitosis (cell division) in the Mar. 4 issue of Nature.¹ Pulling together the latest findings about this elaborate and important process, they begin by describing the puzzle that the cell needs to solve:

At the beginning of mitosis, the process of cell division, chromosomes are organized randomly – like jigsaw puzzle pieces spread out on the floor. Their constituent two ‘sister chromatids’, each of which contains one of the two identical DNA molecules produced by replication, must be oriented such that they will be pulled in opposite directions into the two newly forming cells. Like a jigsaw, the solution for correctly orienting all chromosomes comes partly through trial and error. Mechanisms must exist to eliminate wrong configurations while selecting the right ones.

In the article, they describe how cables (microtubules) connect to handles (kinetochores) on the chromosomes and start pulling them in opposite directions. Another enzyme dissolves the molecular “glue” in the centrosomes that hold the sister chromatids together, so that the opposite poles of the spindle can pull them apart into the daughter cells.

A newly-described “highly-conserved enzyme” (i.e., identical in yeast and vertebrates), named Aurora B kinase, somehow finds chromosomes that lack an attachment to the other pole of the spindle, and fixes them. Apparently this enzyme is able to identify chromosomes that are incorrectly lassoed to the same pole (syntelic attachment) and therefore are not under tension. Only when there is tension on each chromosome, pulling the sister chromatids toward opposite poles, will the process continue. “Finding out how Aurora B identifies and corrects them is an obvious next step,” the authors say.

Ian M. Cheeseman and Arshad Desai, “Cell division: Feeling tense enough?”, Nature 428, 32 – 33 (04 March 2004); doi:10.1038/428032b.

First of all, think of how many parts are involved in this process. Then realize that without high fidelity duplication and segregation during cell division, an organism would be subject to cancer, genetic disease or death. Any alleged evolution would quickly come to a grinding halt, because natural selection is highly dependent on accurate replication for selected traits to be preserved.

To visualize what goes on in mitosis, think of the following analogy. (Analogies, though never precise, and inadequate as proofs, can help make complex processes approachable.) Let’s head out West and picture a team of cowboys who need to split a herd of cattle for market. The cattle in our hypothetical herd all have identical twins that are yoked together. They are wandering aimlessly in a corral, and two teams of cowboys are standing at opposite ends of the corral with lassos in hand. On cue, the corral fence (the nuclear membrane) drops. The cowboys immediately go into action, lassoing every cow in sight.

Their goal is to split the herd into identical halves. To accomplish this, each team has to catch one of each pair: Bob, on the north team, lassos one of the twins, and Joe, on the south team, lassos the other. As soon as a cow is caught, the cowboy starts pulling.  Sometimes, however, two guys on the same team catch both twins. That’s when wrangler Chuck (Aurora B kinase) rides through the herd, looking at ropes that aren’t taut, indicating pairs hitched to the same team. Chuck removes one of the ropes and lets the other team lasso the twin. As the ropers keep applying tension, the boss makes sure all the pairs are lined up, each with one rope pulling a cow north and another rope pulling its twin south. Then another wrangler breaks the yokes, and the cowboys wind in their ropes, pulling their half of the herd into the new north and south corrals.

The difference in cells is that they don’t have sentient cowboys with eyes and ears doing the work by using their brains and roping skills. Instead, cables called microtubules extend outward blindly at random from the spindle poles, looking for attachment points on the kinetochores at the middle of the chromosomes. Tension is applied by molecular motors (see 02/25/2003 headline), like winches, that pull the chromatids into the daughter cells. How can a cell make sure one and only one cable gets attached to each chromatid? This is awesome. Consider also that all the machinery, all the ropes, all the winches, all the corrals, all the procedures and everything else is produced by the DNA in the chromosomes, as if the cattle were the master controller and supplier for the cowboys! For photomicrographs of mitosis, see the illustrations at the Florida State University and the University of Maryland websites.

Mitosis is a coordinated team project that is done exactly right by the cell every time it divides. Mistakes by cowboys might mean a lawsuit or the loss of business, but in the cell, a mistake can mean death. The process is amazing enough as described, but then the authors throw in “the rest of the story” to boggle Darwinian minds beyond all hope of recovery. What they described was for yeast – a “primitive” form of life. What happens in vertebrates, like us humans? Get ready:

In contrast to budding yeast, kinetochores of other eukaryotes bind multiple microtubules (about 20 in humans). These larger kinetochores must coordinate all these microtubules and also deal with incorrect attachments in which microtubules from opposite spindle poles connect to a single kinetochore (termed ‘merotely’). Another study, in this month’s Nature Cell Biology, found that Aurora B does not merely detach syntelic kinetochores from microtubules in vertebrates – it orchestrates the coordinated disassembly of all the microtubules that are bound to each kinetochore, so that the syntelically oriented chromosomes move towards the spindle poles before they are bi-oriented.

Although sister kinetochore geometry seems to be dispensable in budding yeasts with their single-microtubule-connected kinetochores, it could contribute to reducing merotely, as implied by the conservation of this aspect of chromosome architecture throughout eukaryotic evolution. Tackling the extra dimension that the multiplicity of microtubule-binding sites at kinetochores introduces will undoubtedly be another brain-teaser – and a particularly important one, too, because the loss of a single chromosome can be lethal, and aberrant numbers of chromosomes can contribute to birth defects and cancer.

Isn’t evolution wonderful. It blindly found a way to solve multi-dimensional jigsaw puzzles correctly every time, and hung onto its invention for millions of years. It started a successful cattle ranching business, employing blind cowboys. Its advertisement boasts, “Satisfying customers since 2 billion years B.C.” Would you trust such hype?

One last thought. Remember the 02/13/2003 headline last year? It reported that meiosis (cell division for sexual reproduction) is even “much more complex” than mitosis, but there was no evidence it had evolved from the “simpler” process of mitosis.  These are bad days to work for Charlie on the Lazy E Ranch. Better quit the outfit while you can and join up with the Boss who knows the business.