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Unusual collaboration untangles knotty problem of DNA
When Lynn Zechiedrich, PhD, explains how DNA gets tangled and linked in the nucleus of a cell, she uses coiled telephone cords and a box. As she shakes the cords in the box, the coils become enmeshed and even knotted. “Exactly!” she said, when an observer pointed out the knots and tangles. Unknotting those coils quickly – as when the cell begins to divide and replicate –could be a difficult problem, but topoisomerase, an enzyme with a passion for untangling DNA, solves it expeditiously. The mystery lies in how it accomplishes its task. Finding a solution took the talents of Zechiedrich, an assistant professor of microbiology and virology at Baylor College of Medicine in Houston, and Gregory R. Buck, PhD, professor and chair of the mathematics department at Saint Anselm College in Manchester, N.H. Buck is a mathematician who specializes in knot theory. The unlikely collaboration between the two was just what the problem needed. The report on her collaboration with Buck appears in this month’s issue of the Journal of Molecular Biology. “Think about untangling your garden hose in the spring,” said Zechiedrich. “It has been packed away in a small space and everything’s all tangled together. It’s the same with DNA.” Lots of DNA, small space
It may be the same in the abstract, but the situation with DNA is magnified by the amount of material crammed into a tiny, tiny space. The nucleus of the cell contains approximately three meters of DNA. That nucleus, however, has a diameter of between 10 and 20 micrometers (one-millionth of a meter). Imagine how crowded it must be inside that small space, which also includes various other organelles important to maintaining the cell’s normal activities. The genetic material is looped and coiled and folded to the nth degree. To add to the confusion, it is also in constant motion. Chemical machines travel along the DNA, interpreting it, copying it, sometimes repairing it, and always pushing aside the crowded strands as they move on. Understanding how this DNA becomes untangled so that it can be copied during reproduction is important in developing new treatments for cancer and infectious diseases. In both, fast-growing abnormal cells quite different from the normal cells of the human body threaten to outgrow and overwhelm living organisms. That rapid growth is an obvious target of drugs that stop both cancer and infection. In many circumstances, the drugs interfere with the topoisomerases that untangle the DNA. If the DNA cannot be untangled, reproduction does not occur. The cancer dies. The drugs, however, cannot distinguish between cancer and normal cells. They attack all rapidly dividing cells, including healthy ones. Better drugs would be able to distinguish healthy from cancer cells. Before scientists can design them, they have to understand each increment of the action of the DNA-untangling enzyme. The topic is one which Zechiedrich has studied for some time, focusing on understanding each step in the DNA untangling process. When the cell reproduces, the DNA separates into chromosomes that are then duplicated. As the cells split, one of each duplicate pair of chromosome goes to the newly made cells so that each has the same number as the parent cells. Accomplishing this requires untangling the DNA. Cutting through the knots
Topoisomerase cuts through those pieces of DNA that linked through one another and then reconnects the appropriate pieces afterward. Without some discrimination, the action could tangle DNA as much as it untangles it. How does this enzyme differentiate between the knotted and unknotted pieces of genetic material? Zechiedrich and Buck decided that the answer probably lies in the geometry of the DNA strands. Strands that curve toward each other tend to be linked, but those that curve away tend not to be, said Zechiedrich. In addition, the linked strands stay together longer than unlinked ones. This can be seen by pulling on a tangled cord. The longer the pieces of DNA are linked, the greater opportunity the topoisomerase has to act on the tangled strands. Zechiedrich had always tackled the problem from the biological perspective. She was puzzling over the problem when she met Buck at a conference designed to bring mathematicians and biologists together. During a break in the program, “he asked me to explain the big unsolved problem,” said Zechiedrich, whose undergraduate education included a minor in math. That interaction sparked a two-year partnership by telephone and email. Without the conference sponsored by the Burroughs Wellcome Fund, the partnership would never have occurred. This research was funded by the National Science Foundation. The full article is available at http://www.sciencedirect.com/science/journal/00222836.
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