Caltech Chemists Design Molecule To Repair a Type of DNA Damage

PASADENA—Chemists have found a way to repair DNA molecules that have been damaged by ultraviolet radiation. The research is reported in the March 7, 1997, issue of the journal Science.

In the cover article, California Institute of Technology Professor of Chemistry Jacqueline K. Barton and her coworkers Peter J. Dandliker, a postdoctoral associate, and R. Erik Holmlin, a graduate student, report that the new procedure reverses thymine dimers, a well-known type of DNA abnormality caused by exposure to ultraviolet light. By designing a synthetic molecule containing rhodium, the researchers have succeeded in repairing the damage and returning the DNA to its normal state.

The research is also significant in that the rhodium complex can be attached to the end of the DNA strand and repair the damaged site even when it is much farther up the helix.

"What I think is exciting is that we can use the DNA to carry out chemistry at a distance," says Barton. "What we're really doing is transferring information along the helix."

A healthy DNA molecule appears something like a twisted ladder. The two "rails" of the ladder, the DNA backbone are connected with "rungs," the DNA bases adenine, thymine, cytosine and guanine, which are paired together in units called base pairs to form the helical stack.

Thymine dimers occur when two neighboring thymines on the same strand become linked together. The dimer, once formed, leads to mutations because of mispairings when new DNA is made. If the thymine dimers are not repaired, mutations and cancer can result.

The new method repairs the thymine dimers at the very first stage, before mutations can develop. The rhodium complex is exposed to normal visible light, which triggers an electron transfer reaction to repair the thymine dimer. The rhodium complex can either act locally on a thymine dimer lesion on the DNA strand, or can be tethered to the end of the DNA helix to work at a distance.

In the latter case, the electron works its way through the stack of base pairs. The repair efficiency doesn't decrease as the tether point is moved away from the site of damage, the researchers have found. However, the efficiency of the reaction is diminished when the base pair stack, the pathway for electron transfer, is disrupted.

"This argues that the radical, or electron hole, is migrating through the base pairs," Barton says. "Whether electron transfer reactions on DNA also occur in nature is something we need to find out. We have found that this feature of DNA allows one to carry out chemical reactions from a distance."

Barton cautions that the discovery does not represent a new form of chemotherapy. However, the research could point to new protocols for dealing with the molecular changes that precede mutations and cancer.

"This could give us a framework to consider new strategies," she says. This research was funded by the National Institutes of Health. Dandliker is a fellow of the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation, and Holmlin is a National Science Foundation predoctoral fellow.