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Unusual mechanism keeps repair protein accurate

Cancer researchers have discovered that a recently identified protein critical for repairing damaged genes uses an unusual mechanism to keep its repairs accurate.

The protein, called DNA polymerase lambda, is one of a group of proteins known as DNA polymerases that are vital for accurately making and repairing DNA.

But while other DNA-repair proteins insure their accuracy with the help of so-called proof-reading regions or accessory molecules, this protein maintains its accuracy using an otherwise ordinary-looking portion of its molecular structure.

The study was led by Zucai Suo, assistant professor of biochemistry and a researcher with the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. The research, published in the July 14 issue of The Journal of Biological Chemistry, provides new insights into how cells repair damaged DNA.

“DNA is constantly attacked and damaged by a variety of agents,” Suo says. “The body must properly repair that damage, or it can lead to cell death or to cancer, birth defects and other diseases.

“There are six families of DNA polymerases,” Suo says, “and this is the first polymerase to use this mechanism to maintain its accuracy when making new DNA. It is both surprising and unprecedented.”

The repair protein itself was first discovered by scientists studying DNA sequence data produced by the Human Genome Project. Suo and his colleagues then became interested in learning how the repair protein worked.

The protein has four distinct regions, or domains. Three of the regions had molecular structures that strongly suggest the task they performed.

For example, regions three and four closely resemble a well-known repair protein called DNA polymerase beta. In fact, it was this similarity that tipped off scientists that the new protein was probably involved in DNA repair.

Region one also had a predicted structure that should allow it to “dock” with other proteins. “This suggests that this protein may do more than just fix DNA damage,” Suo says.

Region two held the surprise. It is called the proline-rich domain because it has high levels of the amino acid proline.

“There was no known function for a structure like the proline-rich domain, so we at first thought it did nothing more than connect the docking region of the protein with regions three and four,” Suo says.

“Then by accident we learned that this was not just a structural connection, but that it is critical to the protein's ability to replicate DNA with very few mistakes.”

For this study, Suo and his colleagues wanted to learn how efficiently the new protein made new DNA. But the researchers initially considered the protein too large and difficult to produce in the laboratory. So instead of making the entire protein, the researchers made only the part that does the repair work, regions three and four.

When they tested this short version of the protein, however, they found that it made up to a 100 times more mistakes than did the similar repair protein, DNA polymerase beta.

“That error rate is too high,” Suo says. “If the entire repair protein produced that many errors, it would cause more problems than it would fix.”

Next, the researchers made the entire protein and found that it could repair DNA as accurately as the comparison protein.

Last, they tested a version of the protein that lacked the docking region. This shortened molecule also accurately made DNA.

“To find that the proline-rich domain was responsible for this repair protein's high fidelity came as a complete surprise,” Suo says.

Presently the scientists are studying the three-dimensional structure of the entire protein to learn how the presence of a proline-rich region influences the ability of the protein to accurately make DNA.

Funding from the National Institutes of Health Chemistry and Biology Interface Program and from the American Heart Association Predoctoral Fellowship program supported this research.

Darrell E. Ward | EurekAlert!
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