A new twist: Molecular machines that loop chromosomes also twist DNA

Scientists at Delft University of Technology’s Kavli Institute and IMP Vienna Biocenter have discovered new properties of the molecular motors that shape our chromosomes. Six years ago, they discovered that these so-called SMC motor proteins form long loops within human DNA, but now they also discover that these motors also add significant twists to the loops they form. I discovered it.

These discoveries will help us better understand the structure and function of chromosomes. It also provides insight into how disruption of twisted DNA loops can impact health, for example in developmental diseases such as ‘cohesinopathy’. The scientists published their findings in Science Advances.

Imagine fitting a two meter rope into a space much smaller than the tip of a needle. This is the challenge every cell in your body faces as it packs its DNA into its tiny nucleus. To achieve this, nature employs ingenious strategies, such as twisting DNA into coils of coils, so-called “supercoils” and wrapping them around special proteins for compact storage.

Small DNA loops regulate chromosome function

However, compression alone is not enough. Cells also need to adjust the structure of their chromosomes to enable their function. For example, when you need to access genetic information, your DNA is read locally. In particular, when a cell divides, its DNA must first be thawed, replicated, and then properly separated into two new cells.

A specialized protein machinery called the SMC complex (maintaining structure of chromosomes) plays a key role in these processes. Just a few years ago, Delft and other scientists discovered that these SMC proteins are molecular motors that create long loops in DNA, and that these loops are important regulators of chromosome function.

In Cees Dekker’s lab at Delft University of Technology, postdoctoral researchers Richard Janissen and Roman Barth are providing clues to solving this puzzle. They developed a new method that uses “magnetic tweezers” that allow them to watch individual SMC proteins perform loop steps within the DNA.

Importantly, they were also able to determine whether SMC proteins change the twist in DNA. And surprisingly, the research team discovered that it is possible. The human SMC protein cohesin actually not only pulls the DNA into the loop, but also twists the DNA 0.6 turns counterclockwise with each step of creating the loop.

A glimpse into the evolution of SMC proteins

Additionally, the researchers discovered that this body twisting behavior is not unique to humans. Similar SMC proteins in yeast behave in the same way. Remarkably, the different types of SMC proteins from humans and yeast all apply the same amount of twist, rotating the DNA 0.6 times for each DNA loop extrusion step. This indicates that the mechanisms of DNA extrusion and twisting have remained the same for a very long time during evolution.

Whether DNA is looped in humans, yeast, or other cells, nature employs the same strategy.

These new findings will provide important clues to elucidate the molecular mechanism of this new type of motor. Furthermore, we found that DNA loops also affect the supercoiling state of chromosomes, which directly affects processes such as gene expression.

Finally, these SMC proteins are associated with various diseases such as Cornelia de Lange syndrome, and a deeper understanding of these processes is essential to trace the molecular origins of these serious diseases.