Writing here recently, I compared a cell undergoing mitosis to a ranch where cowboys herd chromosomes into separate corrals. If the research behind that article was not enough to inspire awe, there’s a lot more. Here are summaries of other research papers concerning cell division.

Error Correction and Checkpoints

A paper in PNAS addresses the question of how the spindle attaches to the chromosomes and performs “error correction.” The spindle is a spoke-like structure that grows out from the centrioles within the centrosome. Spindle fibers, made up of microtubules (long chains of tubulin proteins that grow and shrink dynamically), grow toward the chromosomes, which are lined up in pairs along the central axis (this after all the DNA has been duplicated and supercoiled into the familiar X-shaped chromosomes). Each chromatid (one on each side, connected by a centromere) must attach to one and only one spindle microtubule. But they don’t start out that way; one chromatid might have several, and others have none. In the paper, Ha et al. wondered how they end up just right. How do attachment errors get fixed?

The mitotic spindle is a bipolar structure, primarily composed of microtubules, that segregates an equal number of chromosomes to each daughter cell with remarkable fidelity. The spindle begins with many incorrect attachments between chromosomes and microtubules, which are corrected over time to eventually satisfy the spindle assembly checkpoint and allow the cell to proceed to segregate the chromosomes. Chromosome missegregation is often attributed to defects in error correction. Despite the widespread importance of chromosome segregation errors, there is currently a lack of quantitative methods to characterize the dynamics of the error correction process and how it can go wrong. [Emphasis added.]

A checkpoint! What a concept! The cell has numerous go/no-go checkpoints that will not allow cell division to proceed until errors are fixed. This sounds like automated quality control by someone who had foresight to know “how it can go wrong” and engineered “error correction” to prevent failure. How could a blind Darwinian processes ever come up with checkpoints?

The authors learned that “error correction is a chromosome-autonomous process that occurs at a constant rate during spindle assembly.” Surely, though, other processes are watching and supervising, because checkpoints and error correction defy Darwinian explanations.

Speaking of checkpoints, researchers at the University of Duisburg-Essen announced the identification of one of the proteins that gives the all-clear signal for mitosis. The default condition is no-go, or stop. “They discovered how the initiator of the stop signal, a protein kinase called Mps1, is bound to the attachment site of the chromosomes and how it is only dislodged once the chromosomes are correctly bound to the mitotic spindle.” The findings were detailed in a paper in Current Biology.

Springs and Bottlebrushes in the Centromere

A Dispatch by Kerry Bloom in Current Biology reported on work showing that the “yokes” in my analogy (the centromeres) have a springiness to them that aids in creating the proper tension on the ropes before the “cowboys” winch them apart. This paper underscores the role of proteins as physical structures able to mediate forces on other molecules.

Turning centromere DNA into a mechanical spring is central to the fidelity of chromosome segregation. A recent study shows how centromere DNA loops and partitioning cohesin and condensin convert centromeres and pericentromeres into bipartite bottlebrushes.

Bloom shows a diagram of the “bottlebrush” shape of these centromere proteins. The shape, consisting of spaced loops in the protein, confers flexibility on the centromere, keeping it stiff but springy enough to hang onto “floppy” DNA strands. 

Each of the centromere domains forms what is known as a bottlebrush. A bottlebrush (Figure 1) is the physicist’s solution to transform a floppy polymer into a mechanical spring. Crowding of side chains (DNA loops) from a primary axis reduces fluctuations along the axis and generate tensile strength. As the primary axis bends, the distance between the side chains is reduced in the direction of the bend, increasing crowding between the side chains that in turn resist the bend.

See here for more on cohesin and condensin, two essential proteins involved in DNA packing, “one of the supreme wonders of nature.”

The paper mentions a potential function for noncoding DNA in the centromere: packing material! Addressing the question of why centromeres differ in size, he writes,

Centromeres are enigmatic from the sequence perspective as well. They can be as small as 117 bp (budding yeast), and up to several megabases in humans. They can be built on unique sequences or hierarchical arrays of small satellite repeats (171 bp alpha-satellite). This paradox can be resolved by distinguishing between the platform for kinetochore assembly and microtubule binding from the bolus of DNA used to form the spring…. Whether the pericentromere is composed of repeat sequences or not is a secondary feature that differs throughout eukaryotic phylogeny.

Tethering Together

Another paper in Current Biology discussed the role of centromere pairing in meiosis, the cell division process for sexual reproduction. Evatt et al. found that “elastic tethers” form between paired chromosomes, and that these chromatin tethers depend on cohesin. The tethers allow chromosomes to orient properly on the spindle. For more on tethers in biochemistry, see this article.

Cohesin’s Work Is Never Done

A paper in PNAS told how preparation for cell division is an ongoing process during interphase — the period between cell divisions. “Activity-driven organization” involves multiple steps, requiring ATP for energy, include “compaction, segregation, and entanglement suppression.” It reminds me of how the Rose Parade Committee starts planning for the next parade as soon as the last one is over. More foresight was required to see the need for these processes. 

Once again, cohesin plays a major role throughout the cell cycle. “Our model suggests that the fast kinetics of active loop extrusion compared to the slow relaxation of chromatin loops maintains a dense chromatin organization,” say Chan and Rubenstien. “This work presents a physical framework explaining how cohesin contributes to effective transcriptional regulation.” See here for how loop extrusion is a clever process used by engineers to prevent damage to computer tapes. The cell uses this strategy to safeguard DNA from breakage during transcription and replication.

Countdown Hold

Reminiscent of a countdown hold for final checks at a launch pad, mammalian cells can linger in a quiescent state before throwing the “master switch” to launch into mitosis. Researchers at Weill Cornell Medicine found that the master switch E2F, a transcription factor protein, can “remain in a potentially lengthy state of partial and reversible activation” before becoming fully engaged. It reminds me of a flight controller at NASA querying all the subsystem engineers to shout “Go!” before commitment to launch.

It seems likely, according to the researchers, that this intermediate primed state allows cells time to sense and integrate the usual, fluctuating cell division input signals, smoothing this “noise” and reducing the chance of inappropriate division. But the researchers suspect that this state has other functions too, including to facilitate DNA repair, since cells in this state show signs of activated DNA-repair processes. 

Summing Up

None of the papers cited in this article appealed to evolution to explain the findings. As usual, the quantity of Darwinese is inversely proportional to the amount of biological detail in a research paper. Intelligent design (foresight, function, and finesse) is found in the details.