Understanding DNA tangle could open door to new treatments for cancer, infectious diseases

HOUSTON -- (March 14, 2006) -- Whether things are linked or not linked globally depends upon how they touch each other. If two things meet and are curved toward each other, they will be linked; if two things meet and curve away from each other, they will not be linked - ever.

It's a simple concept, but for Baylor College of Medicine researcher Dr. Lynn Zechiedrich and her colleagues, it's evidence that untangling DNA during cell division is a more defined process than previously thought - a notion the assistant professor of molecular virology and microbiology proposed in an earlier conceptual report with Dr. Gregory Buck of St. Anselm College, N.H.

In this study appearing in the current issue of Biophysical Journal, Zechiedrich and co-authors Drs. Zhirong Liu and Hue Sun Chan, postdoctoral fellow and professor in the Department of Biochemistry at the University of Toronto, tested the notion. They used a powerful computer cluster to simulate a huge number of linked and unlinked loops (similar to DNA strands). Loops with different shapes were generated over and over again until they could almost fill a room. Their calculations showed DNA molecules that are linked together tend to touch each other in an easily recognizable hook-like way. In contrast, the touching parts of DNA molecules that are unlinked tend to curve away from each other, a feature the researchers call a "free" juxtaposition.

This distinction makes life much simpler for topoisomerases, the enzymes charged with identifying the pieces of DNA that are linked together, cutting them apart and then reconnecting them so that the DNA can separate into untangled lengths that are chromosomes. During cell divisions, the chromosomes are duplicated to become the genetic blueprint of daughter cells.

The problem is that about three meters of DNA is crammed into the cell's nucleus. The nucleus is only a tiny portion of a cell that measures between 10 and 20 microns or one-millionth of a meter. That means that the DNA is folded and superfolded, looped and coiled to the nth degree - all while it is in motion. Finding out how DNA manages to become single strands that enable cell duplication is critical in designing new drugs to treat cancer and infectious diseases.

In this study, Zechiedrich and her co-authors used a computational technique called lattice modeling to determine what happens when the loops of DNA are linked and what happens when they are not linked but are juxtaposed at different angles. When a "hooked" juxtaposition is observed, it is overwhelmingly likely that the two loops are linked. This holds even as the amount of DNA or loops (in the computer's case) continue to pile up.

"The topoisomerases are recognizing the hooked versus free juxtapositions, no matter how much of the material piles up," said Zechiedrich. "The results of this computer simulation are very striking. One link could keep a cell from dividing. Two links is even more lethal. "

Coming from a theoretical physics background, Chan commented that it is very "smart" for nature to have apparently exploited this principle for eons to allow life to flourish. "Now that we have learnt more about it, the same principle can be applied to other areas of science and engineering to address various entanglement problems," said Chan.

Zechiedrich said, "You would think that if the DNA molecules got big enough, it would become impossible to predict from a local juxtaposition whether the DNA molecules are linked or unlinked, but our general analysis shows that it did not. This has important implications as to how we understand packing of this big, long skinny string into any cell."

The fact that cells with linked DNA won't grow means that this knowledge is critically relevant for understanding cancer, for example, said Zechiedrich.

"Can we use some trick to make the DNA linked so we can knock the cancer out?" Funding for this research came from the National Science Foundation, the National Institutes of Health, the Burroughs Wellcome Fund and the Canadian Institutes of Health Research.