DNA repair enzyme: a structure revealed.

Like any complex machine, DNA has a tendency to break down--particularly under the onslaught of ultraviolet light.

Energetic UV rays from the sun create subtle glitches in the fragile genetic material present in every living cell. Left uncorrected, these glitches can eventually lead to biological disaster. Researchers have long known that intense or prolonged exposure of unprotected healthy cells to UV light and other forms of high-energy radiation can lead to cellular mutations and cancer.

Interestingly, nature has evolved at least one countermeasure to address this problem: the enzyme photolyase, which finds and corrects some of the damage to DNA caused by UV exposure. Present in many organisms--including bacteria, goldfish, rattlesnakes, and marsupials--photolyase meticulously snoops around fragile genes, detecting and fixing a specific type of UV-induced error. Unfortunately, people don't produce photolyase.

Hee-Won Park, a biochemist at the University of Texas Southwestern Medical Center in Dallas, and his colleagues have determined the structure of this intriguing enzyme, they report in the June 30 Science. By means of X-ray crystallography, the researchers have achieved a complete three-dimensional analysis of the enzyme's structure and binding site, using a form of photolyase culled from the bacterium Escherichia coli.

"This is a landmark in the field of DNA repair," says John E. Hearst, a chemist at the University of California, Berkeley. "Photolyase is a fundamentally important enzyme.

"Given growing concerns about exposure to UV light, particularly with the thinning ozone layer in the upper atmosphere," Hearst adds, "this enzyme shows us one mechanism by which organisms can protect themselves from UV damage to their DNA."

Ultraviolet radiation disrupts the structure of DNA by causing a chemical reaction that hooks together two distinct bases, forming a so-called pyrimidine dimer. "Pyrimidine dimers kill cells by blocking DNA replication and transcription," says Hearst, and by causing mutations. Photolyase comes to the rescue in a process called photoreactivation. The enzyme binds to damaged DNA, draws energy from light to break apart the offending dimer, then disengages from the double helix.

"The observation of photoreactivation many years ago was one of the first indications to biologists that DNA repair mechanisms exist," says coauthor Johann Deisenhofer, a biochemist at the Howard Hughes Medical Institute at Southwestern Medical Center. "Because this enzyme does not occur in humans, some people may consider it unimportant. Yet it has rather wide distribution in the biosphere, up to marsupials. It appears that placental mammals lost this gene during evolution, though we don't know why that happened."

The enzyme's use of energy from light to drive its repair activities "is quite unusual," Deisenhofer adds. "To my knowledge, there are only two known enzymes that operate this way. The other one is involved in photosynthesis."

While the scientists have no immediate applications in mind for their discovery, Hearst speculates that some biologists may attempt to transfer the gene governing this DNA repair mechanism into organisms lacking the enzyme "to see to what extent the gene protects them from UV damage.

"There's particular interest in protecting plants from ultraviolet exposure," Hearst continues. "DNA repair is such a fundamental aspect of biology that knowing the mechanism by which this repair takes place may give us insights into protection [in humans] against DNA errors and mutations."