A startling new view of the chemistry of DNA is now taking shape as a result of research in the laboratory of long-time NIGMS grantee Jacqueline Barton, Ph.D., at the California Institute of Technology. Last summer, in findings that challenge a longstanding paradigm, Dr. Barton demonstrated that the most common form of DNA can conduct electrons. In papers published in Science and Nature, she reported that when electrons are conducted along the DNA molecule, damage can appear at a site some distance away from the site where whatever initiated the damage-causing event made contact with the DNA. Before Dr. Barton's experiments, many scientists believed that DNA molecules, like proteins, were electron resistors, rather than conductors. Although the proposition that DNA can conduct electrons is still not completely accepted by everyone in the scientific establishment, it is becoming more likely with each paper Dr. Barton's lab publishes.
In a more recent Science paper, Dr. Barton's group presented evidence that a chemical complex artificially attached to one part of a DNA helix can (by electron transfer) repair damage that occurred a long way down the molecule. The kind of damage repaired is the main type of DNA damage caused by the sun's ultraviolet rays. Thus, in addition to reinforcing Dr. Barton's claim that electrons can travel quickly and easily along the DNA molecule, this work may lead to therapies for diseases that involve severe sun damage. It should also improve scientists' understanding of DNA damage induced by radiation and other cancer-causing substances.
In the 1980's, Dr. Barton synthesized molecular complexes containing metal and organic compounds that have the ability to insert themselves between the base pairs of the DNA ladder and cause chemical reactions. She first used these to study DNA structure. Now, she is using similar complexes in her studies of electron conductivity in DNA.
In 1996, Dr. Barton showed that the rate of electron transfer is surprisingly fast and that the amount of damage generated appears to depend on the chemical and structural properties of the DNA rather than on the distance that the electrons travel. Her work also showed that the electron mobility is highly sensitive to distortions in DNA shape and depends on how the bases within the DNA helix are stacked.
Her current studies of DNA repair from a distance also show that repair efficiency does not decrease when the distance between the DNA-bound complex and the site of the damage is increased. Efficiency does decrease, however, when the intervening stack of DNA bases is disrupted by bulges.
Although the method by which the electrons travel through the double helix isn't yet understood, this work may make it possible for scientists to develop new and more sensitive biological probes as well as to design molecules that can undertake therapeutic DNA repair.
REFERENCES
Hall D, Holmlin RE, Barton JK. Oxidative DNA Damage Through Long-Range Electron Transfer. Nature 1996;382:73-5.
Arkin MR, Stemp EDA, Holmlin RE, Barton JK, Hormann A, Olson EJC, Barbara PF. Rates of DNA-Mediated Electron Transfer Between Metallointercalators. Science 1996;273:475-80.
Dandliker PJ, Holmlin RE, Barton JK. Oxidative Thymine Dimer Repair in the DNA Helix. Science 1997;275:1465-8.
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