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04May 2017

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NKI researchers unravel mechanism by which DNA forms loops


Each tiny cell in our body contains 2 meters of DNA. For this to fit, the DNA needs to be very tightly packed. It is crucial that this is done in such a way that the DNA can properly function. A team of researchers from the Netherlands Cancer Institute has uncovered the basic principles driving an important packing-mechanism: the formation of loops. Their work was published in Cell on May 4th.

The research groups involved include those of Benjamin Rowland and Elzo de Wit; the first authors of the paper in Cell are Judith Haarhuis and Robin van der Weide. Together, they set out to test a model of DNA loop formation called the 'loop extrusion model', that was proposed more than 15 years ago. In the loop extrusion model a ring-shaped protein complex called cohesin plays a central role.

Cohesin is often found at the base of DNA loops. The idea of the loop extrusion model is that cohesin is loaded onto small bumps in the DNA by a complex known as SCC2/SCC4, after which cohesin promotes the formation and enlargement of loops. According to the model, as long as cohesin is attached, DNA can slide through the ring, leading to increasingly larger loops. This will stop when a protein called WAPL opens up the cohesin ring and releases it from the DNA.

"Our data strongly suggest that this model actually is correct", comments Rowland. "With a number of different experiments we have shown that the longer cohesin embraces the base of the loop, the larger the loops will get; that WAPL by releasing cohesin limits the enlargement of loops; and that SCC2/SCC4 promotes loop extension."

 "What is also interesting, is that we noticed that without WAPL, the loops continue to elongate beyond known natural barriers consisting of CTCF proteins attached to the DNA.", says Rowland. "Our findings therefore also tell us a lot about how these barriers regulate the formation of loops. Disruption of  loops can affect gene regulation and therefore the cell's behavior. So the proper formation of DNA loops is really important."

For the coming years the researchers will continue to investigate the loop formation process, and what happens when the loop formation goes wrong. Rowland: "It will be very exciting to further study these processes, because they are fundamental to all life on earth."     

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