Dynamic Dual Motion Fuels DNA Loop Creation

Researchers from Delft, Vienna, and Lausanne have found that the protein machines structuring our DNA can change their direction. Previously, scientists thought that these SMC motors, which create loops in DNA, could operate solely in one direction. The revelation, published in Cell, is crucial for comprehending how these motors influence our genome and manage our genes.

Linking DNA

“In certain situations, a cell must rapidly adjust which genes need to be activated and which ones need to be silenced, for instance, in response to food, alcohol, or temperature. Cells utilize Structural Maintenance of Chromosomes (SMC) motors that function like switches to connect various regions of DNA,” elucidates first author Roman Barth.

Nevertheless, SMC machines do not inherently know which sections to link. They merely attach at random points on the DNA and begin to shape it into a loop until they reach a juncture at which they must halt. This is why they depend greatly on their ability to probe both ends of the DNA to discover the proper stop indicators.”

Roman Barth, Delft University of Technology

Transmission system

Biophysicists at Delft University of Technology have recently established that SMC motors can change direction, challenging prior assumptions about their functionality. “Our experiments indicate that SMCs temporarily pull DNA from one side, then reverse direction to draw DNA from the opposite side. By doing this, they can gradually pull DNA into a loop from both ends. We validated this behavior across all categories of SMC motors, of which there are numerous,” states Delft professor Cees Dekker, who led the study. “It’s akin to the gearbox of a vehicle: With a manual gear lever, you can make the car move forwards or backwards. We even pinpointed the ‘gear lever’, the protein subunit NIPBL, in the cohesin SMC motor protein.”

Remarkable nanotechnology

To uncover the reverse mechanism of SMC motors, the researchers utilized a sophisticated home-constructed microscope to observe single proteins on distinct DNA strands. This achievement itself is noteworthy, as Barth remarks: “A single cell comprises millions of proteins, and the human organism consists of trillions of cells. Extracting a few proteins and being able to ‘monitor’ them individually is an extraordinary accomplishment in nanotechnology that requires imaging at a scale of nanometers – 100,000 times smaller than a human hair’s width.”

Neurodegenerative conditions

“Once we grasp how SMC molecular motors form DNA, we could begin to explore what goes awry in diseases like cancer and neurodegenerative disorders, and significantly, how to rectify it,” asserts Barth. “For instance, neurodegenerative disorders may stem from improperly regulated genes during early gestation. Specifically, certain severe conditions, such as Cornelia de Lange syndrome, are associated with SMCs, where the motors likely fail to switch correctly in the embryo’s cells.”

Scientific progress

The study ultimately clarifies the confusion within the scientific community concerning various conflicting theories regarding SMC functionality. Initial investigations suggested that SMCs could only move in a single direction, while other studies indicated that they could simultaneously draw DNA from both sides. This finding resolves those discrepancies. Barth states: “Identifying similarities among SMC motors aids in focusing and refining the SMC research domain. We are no longer required to seek a new mechanism for each distinct type of SMC protein. This will also propel the domain toward practical applications. I would be pleased to see this knowledge transition into pharmaceutical companies, medical facilities, and ultimately doctors’ offices.”