This illustration shows how DNA is formed into a loop by the SMC motor protein cohesin (in purple/blue). The purple part of the motor (with a red/green label) is the protein subunit NIPBL, which can reverse the direction of loop formation. Illustration: Cees Dekker lab TU Delft & SciXel.
The protein machines known as SMC motors, which maintain and shape chromosomes by forming loops in DNA, have been found to be capable of reversing direction.
To switch genes on and off, cells use SMC motors (Structural Maintenance of Chromosomes), which connect different parts of the DNA to one another. Until now, researchers assumed that these molecular machines, which form loops in DNA, move in only one direction. A research team led by Delft bionanotechnologist Cees Dekker has now discovered that SMC motors can reverse direction and therefore have the ability to explore both sides of the DNA and form loops until they find the correct stop signal. The team publishes this important finding – which underpins chromosome condensation, recombination, DNA repair and epigenetic silencing of gene expression – on 6 February in the journal Cell (16 January).
‘Our experiments show that SMCs temporarily pull DNA in one direction and then reverse direction to draw in DNA from the other side. In this way, they can pull DNA into a loop from both sides over time. We have established this for all types of SMC motor,’ explains research leader Cees Dekker in an accompanying press release. ‘You can compare it to a gearbox in a car: with a manual gear lever you can drive the car forwards or backwards. We have even identified the gear lever – the protein subunit NIPBL – in the cohesin SMC motor.’
Nanometres
To map the workings of SMC motors, the researchers use an advanced, custom-built microscope that makes it possible to study a single protein on individual DNA molecules. ‘In doing so, we image at a scale of nanometres – a hundred thousand times smaller than the width of a human hair’, says biophysicist and first author Roman Barth, who moved in October from Delft to the University of Washington in the United States as a postdoctoral researcher. In collaboration with researchers from Lausanne and Vienna, experimental measurements were carried out on the three principal members of the SMC family in eukaryotes: condensin and SMC5/6 in yeast cells, and human cohesin.
A representation of the molecular structure of cohesin (PDB 1W1W). Source: Blastwizard, Wikipedia.
For all three, the loop formation they induce in DNA has been shown to be bidirectional, with short phases of loop growth alternating with loop slippage. This points to a shared mechanism of loop extrusion. Only for human cohesin were the researchers able to identify the key molecular factor underlying the change in direction: the large protein NIPBL. The molecular mechanism underlying directional switching in SMC5/6 and condensin in yeast has yet to be found.
See also:
‘Nature publication on loops, flags and tension in DNA’ – News item on the TU Delft website, 13 April 2023