Researchers solve structure of enzyme vital for DNA repair

When dividing cells copy their DNA, mistakes can - and do - occur. To compensate, cells have a built-in system to correct these errors. That correction process isn't thoroughly understood, but researchers are piecing it together bit by bit.

Now, in the latest step toward solving this puzzle, Rockefeller University scientists have determined the shape of a protein that plays a critical role in the process, an enzyme called Rtt109. The results, published today in the Proceedings of the National Academy of Sciences, include a description of Rtt109's structure and a theory of how it works.

During the first phase of cell division, tightly wrapped DNA unwinds itself from around the spool-like histones that help control its gene activity and provide structural support. The DNA is duplicated, and the new strands coil themselves around a freshly manufactured histone complex. But when DNA damage occurs, the cell recognizes the damage and uses Rtt109 to modify the nearest histone. The modification prevents the damaged bit of DNA from wrapping around it too tightly, creating slack that provides access for DNA repair. "It's a very essential process to be able to repair the DNA," says Andre Hoelz, senior author of the paper and a research associate in Gunter Blobel's Laboratory of Cell Biology. "Our study addresses one step of this very complicated process. We figured out how a critical enzyme is regulated."

Determining the structure of Rtt109 and understanding its regulation is key to understanding the complex DNA damage repair machinery, which involves dozens of other proteins working together. "Solving one structure gives you just a snapshot. But if you have several structures, you can understand how they work," says Hoelz, who collaborated with first author Pete Stavropoulos, a former graduate fellow in the Blobel lab. And by amassing enough data, researchers can begin to understand how other enzymes may be regulated as well.

The research could ultimately lead to the development of drugs for conditions such as cancer, in which rapid cell division goes unchecked and DNA damage from chemotherapy is quickly repaired. "If we can find a way to target the machinery that corrects damage happening during cell division, we could specifically kill those cells undergoing rapid division," Hoelz says.