Researchers clarify proteins’ importance for cancer

In back-to-back reports in Science and Cell, researchers at the UW Medical School describe important new data on proteins that detect and repair gene damage.

The findings provide direct evidence for the cause of a genetic disorder that greatly increases the risk of cancer, called Nijmegen Breakage Syndrome (NBS), as well as broader insights into a fundamental system that can lead to malignancy when it fails to function properly. The Wisconsin research is featured on the cover of the current (May 1) issue of Cell, and appeared in the April 24 Science.

NBS is a rare genetic disorder, similar and probably related to the more common ataxia telangiectasia (AT). Patients with both diseases are extremely susceptible to cancer and can become severely ill if they undergo radiation therapy.

In everyday life, cells experience a moderate degree of chromosome damage through exposure to environmental chemicals, radiation and the natural byproducts of normal cellular processes. Cells constantly monitor the chromosomes, activating DNA repair systems to fix the damage once it’s detected.

DNA repair systems are also responsible for regulating DNA recombination, a process during which genetic information is remodeled and diversified. A defective DNA repair system can throw the cell into serious disarray, and the result can be devastating mutations that may ultimately lead to cancer.

“Cells from NBS and AT patients exhibit fragile chromosomes and it appears they may fail to recognize DNA damage,” said UW Medical School assistant professor of medical genetics John Petrini. “This can lead to high mutation rates and cancer because the cell is simply unable to warn the repair system that damage has occurred.”

Petrini and his team concentrate on MR95, a four-protein complex that controls DNA repair and recombination. The Wisconsin researchers have successfully isolated three of the four proteins from human cells. They also work on the yeast counterpart of the complex, which offers a strikingly parallel model to the human DNA repair system. In the Science article, Petrini’s group developed a novel method for finding and tracking the location of damaged chromosomes. With it, they showed that the MR95 complex moves within the cell to DNA damage sites quickly after the problem occurs.

“This was exciting for a number of reasons, but most of all because it told us that the proteins in the complex must somehow have the ability to rapidly find damaged chromosomes and initiate repair,” he said.

In the Cell study, the researchers identified another protein in the MR95 complex, p95, and demonstrated that it is missing completely in NBS patients.

“NBS cells behave as if they are unable to recognize DNA damage. If you consider that, along with our observation that one function of the repair complex is to find damaged DNA, the two stories begin to mesh into one; namely, MR95 may be important for warning the cell that DNA damage is present,” he said.

The work establishes a solid connection between MR95 and cancer. “A number of inherited cancer syndromes, including familial skin and colon cancer, have been linked to problems with other kinds of DNA repair,”said Petrini. “NBS appears to be the first example of defective DNA recombination that greatly increases the likelihood of malignancy.”