DNA Topology

How does the DNA double helix form knots? Which enzyme ensures that DNA topology is not violated? Professor of Biomedical Engineering at Boston University Maxim Frank-Kamenetskii explains how topoisomerase was discovered.

In less than ten years after molecular biology started in 1962, Max Delbruck made a talk on a mathematical conference. And in this talk he presented the concept of knots in polymers, not in DNA at that time, he just talked about long molecules and said that we now know that biology is based on long molecules, and if there are long molecules, they may be circularized, they may form a circle. And if a molecule forms a circle, the circle may be knotted, it may form a knot. It was a totally abstract idea. He said: “I don’t know whether it is interesting for mathematicians, whether it is interesting from biological view point. I don’t know. I just think that it makes sense to raise this question”.

We assumed that there must be some mechanism in the cell to untie knots. And it actually led to a very exciting chain of events. When people started studying formation of knots in DNA and what’s happens with them, they found that there is a special class of enzymes which were called topoisomerases, which exist in the cell, and their role is to change DNA topology. And later on, already in 1990’s, my former students Alex Vologodskiy and Valentine Rybenkov discovered that these topoisomerases untie knots, they put the system in the equilibrium. Everybody expected that topoisomerases which can change DNA topology, when it is applied to DNA, it will produce equilibrium fraction of the knotted molecule, the same fraction that we calculated in our theoretical simulation. But they found that actually they just untie practically all knots.

The most interesting point about DNA topology is that this enzyme, DNA topoisomerases, which were discovered because of this curiosity of scientists who wanted to figure out whether knots are possible or why are they tied or untied, they proved to be extremely important from the medical view point, because, actually, huge number of chemotherapeutic drugs are actually working on the level of topoisomerases. They interfere when it cuts DNA and then reseal DNA. It is a very vulnerable part of cellular machinery, because if you cut DNA, if you do not reseal it, then you have a double stranded break, the double stranded break is actually absolutely lethal for the cell.