A new twist: the molecular machines that loop our chromosomes also twist DNA

Scientists from the Kavli Institute of Delft University of Technology and the IMP Vienna Biocenter discovered a new property of the molecular motors that shape our chromosomes. While six years ago they found that these so-called SMC motor proteins make long loops in our DNA, they now discovered that these motors also put significant twists into the loops that they form. These findings help us better understand the structure and function of our chromosomes. They also provide insight into how disruption of twisted DNA looping can affect health—for instance, in developmental diseases like ‘cohesinopathies’. The scientists published their findings in Science Advances. 

Small DNA loops regulate chromosome functions

However, compaction isn’t enough. Cells also need to regulate the chromosome structure to enable its function. For example, when genetic information needs to be accessed, the DNA is locally read off. In particular when it’s time for a cell to divide, the DNA must first unpack, duplicate, and then properly separate into two new cells. Specialised protein machines called SMC complexes (Structural Maintenance of Chromosomes) play a critical role in these processes. Just a few years ago, scientists at Delft and other places discovered that these SMC proteins are molecular motors that make long loops in our DNA, and that these loops are the key regulators of chromosome function. 

The struggle of our cells

Imagine trying to fit two meters of rope into a space much smaller than the tip of a needle—that’s the challenge every cell in your body faces when packing its DNA into its tiny nucleus. To achieve this, nature employs ingenious strategies, like twisting the DNA into coils of coils, so-called ‘supercoils’ (see pictures for a visualisation) and wrapping it around special proteins for compact storage.

A new twist

In the lab of Cees Dekker at TU Delft, postdocs Richard Janissen and Roman Barth now provide clues that help to crack this tricky puzzle. They developed a new way to use ‘magnetic tweezers’ by which they could watch individual SMC proteins make looping steps in DNA. Importantly, they were also able to resolve if the SMC protein would change the twist in the DNA. And strikingly, the team found that it did: the human SMC protein cohesin does indeed not only pull DNA into a loop, but also twists the DNA in a left-handed way by 0.6 turns in each step of creating the loop.

A glimpse into the evolution of SMC proteins

What’s more, the team found that this twisting action isn’t unique to humans. Similar SMC proteins in yeast behave the same way. Strikingly, all the various types of SMC proteins from human and yeast add the same amount of twist – they turn DNA 0.6 times at every at every DNA loop extrusion step. This shows that the DNA extrusion and twisting mechanisms stayed the same for very long times during  evolution.  No matter whether DNA is looped in humans, yeast, or any other cell – nature employs the same strategy. 

Essential clues

These new findings will provide essential clues for resolving the molecular mechanism of this new type of motor. Additionally, they make clear that DNA looping also affects the supercoiling state of our chromosomes, which directly affects processes like gene expression. Finally, these SMC proteins are related to various diseases such as Cornelia de Lange Syndrome, and a better understanding of these processes is vital for tracking down the molecular origins of these serious illnesses.

Publicatie:

R. Janissen1,*, R. Barth1,*, I. F. Davidson2, J.-M. Peters2, C. Dekker1,†. All eukaryotic SMC proteins induce a twist of -0.6 at each DNA-loop-extrusion step, Science Advances, 13th December 2024; DOI 10.1126/sciadv.adt1832

^{Affiliations: 1 Department of Bionanoscience, Kavli Institute of Nanoscience Delft, Delft University of Technology, Delft, Netherlands. 2 Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, 1030, Austria. *These authors contributed equally to this work. †Corresponding author: c.dekker@tudelft.nl}