Division Doppelgangers

Alisa Moskaleva


Cyclin A is a confounded nuisance for cell biologists. Noticed serendipitously in 1982 in sea urchins and clams in an experiment that earned a share of the 2001 Nobel Prize in Physiology or Medicine, cyclin A and its doppelganger protein, cyclin B, help cells of all animals grow and divide properly. Cells stockpile both proteins before dividing, use them to control division, and then degrade them after they have served their purpose. If cells are deprived of cyclin A or cyclin B, they can’t divide. If cells have too much of these proteins they start dividing early and get stuck, unable to separate into two new cells. But whereas cyclin B sticks around until the step before the two new cells separate, when the two copies of the cell genome are all set to separate, cyclin A disappears several minutes earlier when those two copies of the genome are nowhere near ready to split. Why does a responsible regulator like cyclin A leave its post so scandalously early? And why does a cell need cyclin A to regulate division when it has cyclin B there willing and present?

Lilian Kabeche and Duane A. Compton begin to answer both of these questions in their October 3 Nature paper. They took a close, microscope-assisted look at what goes on during cell division. The general process of cell division has been known for over a hundred years. Before starting to divide, the cell replicates its contents, including its DNA, so it can pass on a copy to both cells of the new generation. Then, during the prometaphase stage, the cell packs up its DNA really tightly and simultaneously builds up lots of microtubules, which are long fibers of protein that act as miniature ropes and sprout from two opposite sides of the dividing cell. The microtubules attempt to lasso the DNA, so that half of the DNA is attached to microtubules from one end of the cell and the other half is attached to microtubules from the other end of the cell. At this time cyclin A disappears. Then, at a stage called metaphase when the DNA is all lined up in the middle of the cell and properly attached to microtubules, cyclin B disappears. What follows is separation of the two copies of DNA to the two sides of the cell, pulled by microtubules; this is called anaphase. Finally, in telophase the two cells pinch off from each other and resume growing.

Kabeche and Compton focused on how cyclin A may be regulating the way microtubules attach to DNA. The big blob of DNA inside a cell is quite easy to see under a microscope, but it’s much harder to see the thin individual microtubules. Thus, Kabeche and Compton labeled microtubules with a photoactivatable fluorescent protein, a protein that can be made to glow by shining a certain wavelength of light on it. Then they looked for microtubules that approached DNA, shone light on them to make them glow, and assessed whether the glowing microtubules would stay in place or wander off. They observed that in prometaphase microtubules were much more likely to wander off than in metaphase. This makes sense. In metaphase, the DNA is organized and aligned, so it should be easy for microtubules to grab it. In prometaphase, by contrast, the DNA is still unorganized and in the process of aligning, so mistakes in attaching microtubules are likely. Microtubules from both sides of the cell may grab the same copy of DNA. Or microtubules from only one side of the cell may grab both DNA copies. These attachment mistakes, if not corrected, would distribute DNA unevenly or even tear it up, leading to deleterious mutations. So, it’s good that microtubules in prometaphase do not attach stably. When Kabeche and Compton gave cells extra cyclin A, they saw that microtubules would wander much longer than normally even in cells that were in metaphase and had their DNA aligned properly. And when Kabeche and Compton deprived cells of cyclin A, they noticed that the DNA separated unevenly, suggesting that microtubules attached at the wrong place.

All of these observations suggest that cyclin A somehow makes microtubules restless, whereas cyclin B, still present when microtubules make stable attachments, does not. The cell uses cyclin A to control the attachment of microtubules to DNA, and then disposes of it, while relying on cyclin B to control the separation of DNA copies. Given its distinct function, cyclin A disappears not early, but at precisely the right time. If it were to stick around, microtubules would never attach to DNA and division would never proceed. On the other hand, if it were not present at all, microtubules would attach too early and in all the wrong places, leading to mistakes in partitioning the genome to the new generation. Of course, there are many vexing questions that remain to be answered, the most obvious of which is how does cyclin A cause microtubules to no longer attach to DNA? It looks like cyclin A has many more mysteries to reveal.

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