Researchers at the Kavli Institute of Delft University of Technology and the IMP Vienna Biocenter have uncovered a new characteristic of the molecular motors that organize our chromosomes.
Previously, they unveiled that SMC motor proteins create long loops in our DNA. Now, they reveal that these motors also introduce significant twists into these loops.
This new understanding enhances our understanding of chromosome structure and function. Additionally, they offer insights into how disruptions in twisted DNA looping can impact health, particularly in developmental disorders referred to as ‘cohesinopathies.’
While compaction is essential, it’s not sufficient on its own. Cells must also finely tune their chromosome structures to ensure proper function. When it’s time to access genetic information, DNA is read at localized regions. Crucially, before a cell divides, the DNA must untangle, duplicate, and then separate accurately into two new cells.
Specialized protein machines called SMC complexes (Structural Maintenance of Chromosomes) play a critical role in these processes. Recently, scientists at Delft and other institutions discovered that SMC proteins act as molecular motors that create long loops in our DNA, which are essential regulators of chromosome function.
The challenge faced by our cells Envision the task of trying to store two meters of rope in a space significantly smaller than the point of a needle—this is the predicament every cell in your body encounters when trying to package its DNA within its minuscule nucleus. To tackle this, nature employs clever techniques, such as twisting the DNA into coils upon coils, known as ‘supercoils,’ and wrapping it around specific proteins for efficient storage.
In the lab of Cees Dekker at TU Delft, postdocs Richard Janissen and Roman Barth have now provided insights that help address this complex challenge. They pioneered a cutting-edge technique using ‘magnetic tweezers’ to observe individual SMC proteins as they make looping movements in DNA. Critically, they could determine whether these SMC proteins induce changes in the DNA twist.
Their findings were remarkable: the human SMC protein cohesin not only forms loops in the DNA but also introduces a left-handed twist of 0.6 turns with each looping action. These findings offer a fascinating glimpse into the evolutionary history of SMC proteins.
The researchers discovered that this twisting mechanism is not exclusive to human proteins; yeast SMC proteins exhibit the same behavior. Intriguingly, all SMC proteins from both humans and yeast impart an identical twist—0.6 turns during each step of DNA loop extrusion.
This shows that the DNA extrusion and twisting mechanisms stayed the same for a very long time during evolution. No matter whether DNA is looped in humans, yeast, or any other cell – nature employs the same strategy.
The recent discoveries will offer crucial insights into deciphering the molecular mechanism of this novel motor type. Moreover, they highlight that DNA looping influences the supercoiling condition of our chromosomes, which in turn impacts processes such as gene expression.
Lastly, these SMC proteins are associated with several disorders, including Cornelia de Lange Syndrome, and gaining a deeper understanding of these mechanisms is essential for identifying the molecular causes of these serious conditions.
Journal reference:
- Richard Janissen, Roman Barth, Iain F. Davidson, Jan-Michael Peters, Cees Dekker. All eukaryotic SMC proteins induce a twist of −0.6 at each DNA loop extrusion step. Science Advances, 2024; DOI: 10.1126/sciadv.adt1832