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Researchers Discover That Cohesin Stabilizes DNA

Dr. Jan-Michael Peters and his team at the Research Institute of Molecular Pathology (IMP) in Vienna, Austria, have found that the structure of chromosomes is supported by a kind of molecular skeleton, made of cohesin. This discovery was reported online on August 25, 2013 in Nature. Every single cell in the human body contains an entire copy of the genetic blueprint, the DNA. Its total length is about 3.5 meters and all of it has to fit into the cell’s nucleus, just one-hundredth of a millimeter in diameter. Blown up in proportion, this would equal the task of squeezing a 150-km-long string into a soccer ball. Just how the cell manages to wrap up its DNA so tightly is still poorly understood. One way of compacting DNA is achieved by coiling it tightly around histone proteins. This mechanism has been studied in detail and is the focus of an entire discipline, epigenetics. However, simple organisms such as bacteria have to manage their DNA packaging without histones, and even in human cells, histones probably cannot do the job on their own. In its Nature article, Dr. Peters’ IMP research team in Vienna presents evidence for an additional mechanism involved in structuring DNA. IMP Managing Director Dr. Peters and his research group discovered that a protein complex named cohesin has a stabilizing effect on DNA. In evolutionary terms, cohesin is very old and its structure has hardly changed over billions of years. It was present long before histones and might therefore provide an ancient mechanism in shaping DNA. Cell biologists are already familiar with cohesin and its role in cell division. The protein complex is essential for the correct distribution of chromosomes to daughter cells. It forms a molecular ring that keeps sister chromatids together until the precise moment when segregation takes place. This function and the molecular structure of cohesin were discovered by IMP scientists in 1997. Dr. Antonio Tedeschi, a postdoc in Dr. Peters’ group, has now found evidence that cohesin supports the architecture of DNA in non-dividing (interphase) cells. He analyzed cells in which he had shut down the function of Wapl, a protein that controls how tightly cohesin binds to DNA. Without Wapl, cohesin is ‘locked’ onto chromatin in an unusually stable state. As a consequence, cells are unable to express their genes correctly and cannot divide. When he analyzed Wapl-depleted cells under the microscope, Dr. Tedeschi found elongated structures that he called “vermicelli” (Italian for small worms). Because one “vermicello” is present for each chromosome, he concluded that its function is to keep chromosomes in shape, rather like a skeleton. “We think that the vermicelli are the ‘bones’ of interphase chromosomes,” says Dr. Peters. “Just like our bodies depend on the bones for support, the cells depend very much on cohesin to retain their structure.” The importance of the cohesion system becomes obvious in cases where it is impaired. Several rare congenital diseases have been linked to mutations in the respective gene for different proteins in the cohesin complex. The faulty structure of the cohesin molecule causes severe developmental retardation and is a serious medical condition. There are no therapies for this condition available at present. The image is an artistic interpretation of fluorescent light micrographs of Wapl-depleted nuclei which show cohesin vermicelli. The nuclei have been pseudo-colored and scaled to different sizes (Copyright: IMP). [Press release] [Nature abstract]