We finally know how long strands of DNA fold into woolly X’s. It was already known that the shape of chromosomes influences essential processes, such as cell division and turning genes on and off. We also already knew that the protein complex cohesin plays a major role in the folding of chromosomes by bringing DNA strands together. But how cohesin ‘chooses’ which piece of DNA to bind to was a big question.
Two Dutch studies come up with answers: scientists from TU Delft register Nature that how tight the DNA helix is determines how cohesin shapes chromosomes. And at the Netherlands Cancer Institute, researchers found a universal key-lock principle that proteins use to bind cohesin to a piece of DNA. They publish this Nature Structural & Molecular Biology.
Our DNA is divided over several chromosomes, which lie in the cell nucleus as long strands most of the time. But before a cell can divide, such a chromosome must double. “These strings of spaghetti then transform into compact pieces of macaroni,” says Benjamin Rowland, group leader of the research at the NKI. With hands and feet he explains how the DNA is doubled and coiled. The result is two identical chromosomes joined halfway: a woolly X of compact DNA.
Loops in the DNA
A complex of several proteins, cohesin, plays an important role in this: it holds two strands of DNA together like a ring. The complex loops the DNA so it can regulate genes and holds two identical chromosomes together until the cell divides. Another protein, CTCF, determines where the cohesin ring binds to DNA.
“Our assumption was that CTCF simply acts as a stop sign for cohesin, marking where it should create loops in the DNA,” says Cees Dekker, professor of molecular biophysics at TU Delft. The process turned out to be much more dynamic. Dekker: “We discovered by chance that the amount of tension on the piece of DNA influences this blocking function of CTCF. If there is more force on the strand, CTCF stops the loop formation of cohesin. That ultimately has an effect on which genes are switched on and off.”
The tension is caused by protein machines that move over the DNA and, for example, transcribe DNA into RNA. Roman Barth, a lead author of the article, compares CTCF to a traffic light: “Pedestrians pay more attention when the road is busy. You don’t run through red quickly. When many proteins are active on the DNA, there is more tension and cohesin listens better to the CTCF traffic light.”
Two building blocks
Whereas Dekker’s group zoomed in on the level of a single DNA molecule, Rowland’s group investigated the effect of cohesin on the chromosome scale. “In 2020, we exposed how CTCF binds to cohesin: according to a key-lock principle. Two CTCF building blocks fit exactly in a quarry of cohesin,” says Rowland. CTCF is not the only regulator of cohesin. While CTCF binds cohesin to make DNA loops, another protein, SGO1, binds to cohesin to hold chromosomes together for cell division.
The researchers determined the spatial structure of SGO1. To their surprise, the protein turned out to have the same building blocks and thus also fit the cohesin lock as a molecular key. Rowland: “This result was fascinating. In fact, these two proteins seem to be just the tip of the iceberg of a universal mechanism by which cells structure chromosomes.”
Both studies have no direct applications, the scientists say. “It is especially important to understand how cohesin works because it plays such a crucial role in chromosome structure in all organisms,” says Rowland.