Rules of Engagement: How to build a mitotic chromosome

When cells divide – a process called mitosis – the chromosomes become more compact still. How these huge lengths of DNA are packaged to make the chromosomes that must segregate when cells divide has been studied for over 140 years. However, the answer to how the DNA gets folded is still not known.

In a new paper, scientists studied the molecular machines that package DNA to make compacted mitotic chromosomes, providing answers to this long-standing question.

It is well established that four different molecular machines are involved in the process of forming new chromosomes. What had remained unclear until now, was precisely how they work together.

The study reveals that one of them, known as cohesin, does two jobs. When the DNA is copied before cells divide, one type of cohesin forms a ring that holds the two duplicated DNA molecules together. A second type of cohesin then jumps onto single DNA molecules and makes loops that are involved in controlling the expression of genes along the chromosomes. When cells divide, this second cohesin gets kicked off the chromosomes by two other machines called condensin I and II.

To make the discovery, the authors first determined what happened when individual parts of the machinery are removed. They observed how that affects the folding up of the DNA and used sophisticated microscopy methods to see clearly the defective chromosomes in three dimensions.

All of these machines are structurally related to one another. They work by grabbing the DNA and pushing it along, forming a loop. As the loop gets pushed out by the motor, DNA on one or both sides is reeled in. This means that molecular motors bound along the same section of DNA will collide. The purpose of this study was to figure out what happens when the motors run into each other.

The answers were clear. When condensin runs into a cohesin that is involved in regulating gene expression, it kicks the cohesin off the DNA. When condensin runs into the cohesive form of cohesin that holds the two replicated DNA molecules together, it jumps over it. Finally, when condensin molecules run into each other, they get stuck.

Based on these observations made in the laboratory, polymer physicists then created powerful computational models which could predict what the structures of the chromosomes would look like in detail and how they would form.

These increases in our understanding of mitotic chromosome structure and formation were described by one of the anonymous referees as a landmark in our understanding of how chromosomes are formed.

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Bill Earnshaw