USC-led team of scientists recreates DNA-mending pathway in test-tube

Finding could lead to new cancer drugs, more effective radiation treatments

One of five known DNA-repair mechanisms in cells has been completely analyzed and reconstituted in a test tube by an international collaboration of researchers led by scientists from the Keck School of Medicine of the University of Southern California. The team is the first ever to reconstitute this pathway, known as the nonhomologous end joining pathway, or NHEJ, and NHEJ is only the third repair pathway to be reconstituted in the laboratory. The findings were published in the December 3, 2004 issue of Molecular Cell.

Understanding how DNA repair works is critical to understanding the development of cancer, which often occurs when DNA is not properly repaired.

In addition, notes Michael Lieber, M.D., Ph.D., the Rita and Edward Polusky Chair in Basic Cancer Research at the Keck School who heads up the molecular genetics program at the USC/Norris Comprehensive Cancer Center and was principal investigator on this study, the ability to reconstitute the pathway has important practical implications.

“Now we can really test for drugs that will affect the pathway,” he said. “For instance, one of the things this pathway is particularly good at is repairing radiation damage. When people get radiation treatment, both the normal and the tumor cells will use this pathway to resist the radiation. If we could inhibit the pathway regionally in or around the tumor, we could really make radiation dramatically more effective.”

In order for the team to reconstitute the NHEJ pathway, which is found in all cells that are evolutionarily ’above’ yeast, they first had to purify all the proteins used to rejoin the double strands of DNA once they’ve suffered damage and are severed from one another. As it turned out, two of the seven proteins come from a class of polymerases that were discovered in 1999 by Myron Goodman, Ph.D., professor of molecular biology at the USC College of Letters, Arts and Sciences, who became an essential part of this research team. “Before this, no one knew what this class was good for,” Lieber explains. “This is really the first solid indication of what two of these polymerases might do.”

Knowledge of the details of the NHEJ pathway extends beyond its connections to cancer and radiation treatment, Lieber notes. “This pathway gets used not just for accidental damage, oxidative damage and radiation damage to DNA, but is also used in the immune system,” he explains. “So the immune system would function less well without it.”