Baylor Researchers Keep Knots Out of DNA

The compound that unknots bacterial DNA, an enzyme called topoisomerase IV, has been identified by scientists at Baylor College of Medicine.

"For years, textbooks credited gyrase as being the enzyme that unknots the DNA because it did so when experiments were conducted in a test tube. However, when research was conducted inside the cell, we found that the reverse was true - it was actually the hidden enzyme, topoisomerase IV, that untied the knots," said Dr. Lynn Zechiedrich, assistant professor in the Department of Molecular Virology and Microbiology at Baylor, and principal investigator of the study.

Results of the study were recently published in the journal Genes and Development. The most surprising part of the study, Dr. Zechiedrich explained, was finding that the enzyme previously credited with the ability to untie these knots cannot untangle the DNA knots in the cell.

DNA, when stretched out, extends more than a yard in length and exists in a tiny cell, much smaller than a pinhead top, where it must remain untangled in order to carry out functions such as replication and division.

Dr. Zechiedrich said knots are present in all human DNA. However, when the material becomes extremely knotted, healthy cells can be damaged.

"The DNA is a source of information much like an encyclopedia. When the structure becomes tangled, we have special enzymes that remove the tangles so that this encyclopedia, which is a necessary element of genetic makeup, can be read," said Richard Deibler, a graduate student in the cellular and molecular biology program at Baylor and co-author of the study.

The next step in the research, Dr. Zechiedrich explained, is to understand what prevents these enzymes, while inside a test tube, from completing functions.

"We know that these enzymes are capable of carrying out certain reactions under certain conditions, but we still don't know what factors influence these reactions. Therefore, we must study what goes on inside the cell itself," Dr. Zechiedrich said.

Diebler will begin to evaluate the role that enzymes and DNA play when knots exist in the structure. He hopes to determine whether the cellular response will be a mutation, replication or a division.

"We can compare the knots in DNA to knots in a mountain climbing rope - the climber must tie the right knot in the line because if the wrong knot is tied, the rope wraps around itself, cuts itself like scissors, and breaks. This is what we think might be happening with the DNA," Diebler said.

Experiments remain in preliminary stages, but researchers hope that this finding will provide basis for better therapeutic drugs in the future.

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©2006 Texas Medical Center

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