Bidirectional movement drives the formation of the DNA loop

Bidirectional movement drives the formation of the DNA loop

Scientists from Delft, Vienna and Lausanne discovered that the protein machines that shape our DNA can change direction. Until now, researchers believed that these so-called SMC motors, which make loops in DNA, could only move in one direction. The discovery, which will be published incellis key to understanding how these motors shape our genome and regulate our genes.

Connect DNA

"Sometimes a cell needs to quickly change which genes should be expressed and which should be turned off, for example in response to food, alcohol or heat. To turn off genes, cells use structural maintenance of chromosomes (SMC) motors, which behave like switches to connect different parts of the DNA," explains first author Roman Barth.

However, SMC machines do not know which parts to connect. They simply load somewhere on the DNA and start looping it until it reaches a point where it is forced to stop. Therefore, they rely heavily on the ability to explore both sides of DNA to find the right stop signs. “

Roman Barth, Delft University of Technology

Gearbox

Technology biophysicists at the Delft University of Technology have now found that SMC motors can change direction, contrary to what was thought possible. "Our experiments show that SMCs momentarily pull DNA from one side and then switch direction to pull DNA from the opposite side. This way, over time, they can pull DNA from both sides into a loop. We found this to be true for all types of SMC motors, of which there are many," says Delft Professor Cees Dekker, who supervised the research. "You can do it with one Compare gears in a car: A manual gear stick allows you to make the car move forward or backward. We even identified the “gear lever,” the protein subunit NIPBL, in the cohesin SMC motor protein.”

Impressive nanotechnology

To discover the reverse gearing of SMC motors, the researchers used an advanced homemade microscope to examine individual proteins on individual DNA molecules. That in itself is an impressive feat, as Barth explains: "A single cell contains millions of proteins and the human body is made up of trillions of cells. Pulling out a few proteins and being able to observe them individually is a feat of nanotechnology that involves imaging at a scale of nanometers – 100,000 smaller than the width of a human hair."

Neurodegenerative diseases

“Once we understand how SMC molecular motors shape DNA, we may ask what goes wrong in diseases like cancer and neurogenerative diseases, and especially how it can be corrected,” says Barth. “Neurogenerative diseases, for example, can be the result of dysregulated genes in early stages of pregnancy in cells of the embryo.”

Science in action

The study finally resolves the confusion in the scientific community about various conflicting theories about how SMCs work. Early research suggested that SMCs could only move strictly in one direction, while other research suggested that they attracted DNA from both sides simultaneously. The discovery resolves these controversies. Barth: After finding commonalities between SMC engines, it helps to focus and optimize the SMC research field. We no longer need to search for a new mechanism for each individual SMC protein. It will also accelerate the field toward applied science. I. I am glad that this knowledge is entering pharmaceutical companies, hospitals and eventually doctors' offices. “

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