Influence Of A Cancer Inhibitor On A Single DNA Molecule Tracked (8/6/2007)

Researchers in Delft University of Technology's Kavli Institute of Nanoscience have cast new light on the workings of the important cancer inhibitor topotecan. Little had been known about the underlying molecular mechanism, but the Delft scientists can now view the effects of the medicine live at the level of a single DNA molecule. The research has been published online by the journal Nature on 24 June 2007. The lead author of the article, Daniel Koster, received his PhD at TU Delft on Monday 25 June 2007, partly on the results described in the article.

The medicine investigated, topotecan, interacts with an important protein (TopoIB), causing a (cancer) cell to malfunction. The TopoIB protein is responsible for the removal of loops from DNA, which arise amongst other things during cell division. The TopoIB protein binds to the DNA molecule, clamps around it and cuts one of the two DNA strands, after which it allows it to unwind and finally joins the broken ends together.

Until now it has been supposed that topotecan only causes the TopoIB protein to reside longer than normal on the DNA molecule, disturbing the cell division and damaging the (cancer) cell. But the Delft researchers have now discovered to their surprise that adding topotecan also dramatically impedes the unwinding and that DNA loops accumulate as a result. The accumulation of these DNA loops forms the basis for an alternative mechanism, and could help in the development of better cancer medicine.

PhD candidate Daniel Koster, Master's student Elisa Bot and senior lecturer Nynke Dekker of the Molecular Biophysics group of the Kavli Institute of Nanoscience have managed to unravel this mechanism in an extremely direct manner. In the laboratory they fixed a single DNA molecule between a glass plate and a magnetic sphere. With the help of two magnets they could both pull and twist the DNA molecule. When they added TopoIB to a twisted piece of DNA, they saw that the loops were slowly removed.

What is exceptional is that the action of one TopoIB protein on one DNA molecule could be observed live. In collaboration with St. Jude Children's Research Hospital in Memphis (USA) the mechanism could also be observed in living yeast cells.

The research is supported by the Foundation for Fundamental Research on Matter (FOM) and the Netherlands Organisation for Scientific Research (NWO).

Note: This story has been adapted from a news release issued by Delft University of Technology

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