Rings and loops structure the DNA (copyright Benjamin Rowland)
Cohesin has two roles. First it was discovered that the ring plays an important role in cell division. After all 46 chromosomes are copied, they consist of two identical halves: one for each daughter cell. Cohesin rings keep the two copies firmly together until they are pulled apart and the cell can divide in two. Chromosomes have their iconic X-shape because the cohesin rings in the middle remain in place for the longest time. Condensin plays a different role, as it makes the chromosomes short and compact, which is also essential for a successful cell division. If cohesin or condensin does not function properly, the DNA is not accurately distributed over two daughter cells. This can lead to cancer or other detrimental diseases.
But cohesin also does something else: it makes loops in the DNA that increase in size as long as cohesin is on the DNA. This is what Benjamin Rowland's group, in collaboration with Elzo de Wit's group, also in the Netherlands Cancer Institute, demonstrated experimentally last year. They have hereby confirmed a famous hypothesis that was launched in 2001 by the discoverer of cohesin, but that had never been demonstrated in a lab: the loop extrusion model. They also showed that the cell constantly makes loops that are then lost again. All of this keeps the DNA in motion so that genes can be turned on and off.
The researchers know the components of cohesin. They also know which molecule can open the ring, although its mechanism is still unknown. And they know the - severe - consequences when cohesin does not function properly. But how it all really works remains a black box and that needs to change in the coming years. Rowland: 'What is the driving force that leads to the formation of the loops? Does cohesin move along the DNA strand and does it provide the energy by itself? It is a good possibility, but the simple fact is that we just don't know. What role do individual components of the protein complex play? And do the loops in the DNA become larger because more cohesin rings are used, or because cohesin increases its speed?'
'The cool thing about this research is that it is really interdisciplinary', says Rowland. 'We want to know everything about how these processes work, so we use all kinds of techniques to get to our answers. Because these techniques are often very new and specialized, we collaborate with many research groups both inside and outside the Netherlands Cancer Institute.'
A selection of methods and techniques: the researchers look at chromosomes with a super-resolution microscope, use a technique that shows which pieces of DNA interact with other pieces, and do genetic screens that pinpoint which gene is responsible for a process. And then they use biochemistry to figure out the precise mechanism. Rowland: 'With the Consolidator Grant, the ERC finances researchers who have successfully led their own research group for a couple of years. You are assessed by the scientific community. I think it's quite fantastic that eight anonymous referees apparently all really like our research.'