Marjon van Ruiten is conducting her PhD research on the mechanisms by which DNA is packed inside our cells. She is investigating the role of a molecular machine called cohesin, which forms loops in the DNA. Cohesin uses these loops to make the long strands of DNA more compact. The loops provide structure to the DNA and are also important control the activity of genes. Specific DNA segments that may be very far apart have to be brought together to get genes to work. And that is a very precise mechanism.
We only partially understand how these loops are made at the moment. One thing that we have been aware of for some time, however, is that small loops grow bigger and bigger. But as it turns out, there is a brake that will put an end to this. A brake that can be turned on and off. When the brake is on, cohesin cannot enlarge the DNA loops - but as soon as the brake is released, cohesin can proceed to enlarge the loops again.
'We discovered how this brake system works, and how it is regulated within our cells,' says Benjamin Rowland of the Netherlands Cancer Institute. His lab studies the functions of cohesin and related mechanisms. Turning the brakes on and off seems to be a cyclical process.
Two key amino acids regulate this brake system, Marjon van Ruiten discovered with her research in Rowland's lab. What happens then is that these amino acids develop a different electrical charge: a switch from positive to neutral. This causes them to bind to another protein, so that cohesin is no longer active. When the reverse happens, the looping process seems to continue again.'
Now it's important to find out what the consequences of this 'brake-to-no-brake' cycle are on the functioning of cells and organisms. "We don't know that yet," van Ruiten says. 'We do know that we find cohesin mutations in many tumor cells. But we don't know yet whether there is a relationship between this molecular brake and cancer. The Cornelia de Lange syndrome, a serious developmental disorder, does appear to be affected by this brake.'
Changing the electrical charge of the two amino acids is the result of a chemical reaction called acetylation. The reverse, not surprisingly, is called de-acetylation. When the researchers inhibited de-acetylation in cells, they found only short loops in the DNA. 'Acetylation of cohesin is a general phenomenon,' says Marjon van Ruiten. 'Simple single-celled organisms like yeast also experience acetylation. A French lab published a paper in this same issue, in which they show that these molecular brakes in yeast operate in the exact same way. It really seems to be a universal control mechanism that determines the way in which DNA is folded in a wide variety of life forms.'
The picture on the cover of the June issue of Nature Structural & Molecular Biology features a closeup of the brakes on the front wheel of Marjon's road bike. She took the picture because it symbolizes the brakes within cohesin's mechanism. It's even more special that I managed to traverse the Alpe d'Huzes earlier this month with this same bike. The money raised through the Alpe d'Huzes supports new cancer research.
Rowland's research group has previously discovered that cohesin can be halted by a kind of roadblock: proteins that recognize code in specific DNA sequences and cling to them. We also see acetylation occuring during this process, as an additional regulatory mechanism. That is one of the fascinating aspects of our research,' says van Ruiten: 'You keep discovering new layers of control mechanisms that determine the way in which cohesin folds the DNA with great precision. It's quite extraordinary to be able to make discoveries that raise all sorts of important questions, and then to use my own bicycle trip to facilitate further research into the same topic!