NIH And Rockefeller Researchers Find That Gene Acts As "Caretaker" To Genome

"We're learning that chromosomes are constantly breaking and being repaired by these caretaker genes," says co-author Michel Nussenzweig, M.D., Ph.D., Rockefeller professor and investigator with the Howard Hughes Medical Institute. "These genes are crucial for maintaining the integrity of the genome, and if the genes aren't working properly, it can lead to cancer down the road."

The research, reported in the March 30 issue of the journal Nature, was conducted at the National Institutes of Health and led by Andre Nussenzweig, Ph.D., a scientist in the Experimental Immunology Branch of the National Cancer Institute and brother of Michel Nussenzweig.

A number of genes in mammals have been linked to cancer because tumors are more likely to develop if the genes are mutated. In recent years, biologists have classified these "cancer-susceptibility genes" into two groups: "gatekeepers," which act as brakes on uncontrolled cell growth and division, and "caretakers," which keep the body's DNA from breaking or rearranging into the wrong sequence.

The most significant gatekeeper gene identified so far is p53, which was co-discovered by Rockefeller President Arnold J. Levine, Ph.D., in 1979. To protect the body from cancer, the p53 gene watches for cells that contain damaged DNA and either slows their growth until the DNA can be repaired or induces those cells to commit suicide. When a mutation occurs in p53, uncontrolled cell division that would be blocked in a person with a healthy copy of the gene often develops into cancer. Disruption of p53’s normal function is associated with an estimated 60 percent of human cancers.

Ku80 was already known to play an important role in repairing double-strand breaks in DNA, but it was not known until now that it has a caretaker role in preserving the stability of the genome. In the research reported in Nature, Nussenzweig and his colleagues showed that the cells of mice with a mutated Ku80 gene display a marked increase of chromosome breakage and jumbled sequence.

Despite these chromosomal instabilities, mice engineered to lack Ku80 develop cancer only slightly earlier than do normal mice, evidence that absence of Ku80 does not cause tumors directly. Instead, deficiency in Ku80 indirectly leads to tumors because it produces genetic changes that result in increased mutation of other genes, including p53. In this respect, Ku80 resembles the gene called BRCA1, which is well-known for its link to breast cancer.

Mice that are deficient in Ku80 and also have p53 mutations quickly develop tumors that are similar to those found in humans with a disease called Burkitt's lymphoma, in which tumors form in white cells in the blood and lymph glands.

The type of cell affected in Burkitt's lymphoma, the B lymphocyte, is normally involved in fighting infection by producing antibodies, the body’s defense against foreign intruders. The study suggests that Ku80 and p53 normally cooperate to prevent double-strand breaks in DNA from developing into tumors.

"While deficiency in p53 increases the risk of a broad range of cancers, deficiency in p53 and Ku80 is linked to more specific kinds of tumors," Nussenzweig says. "One hallmark of these tumors is that chromosome segments are out of order, suggesting that Ku80 normally functions to keep everything unbroken and in the right place."

In addition to Andre and Michel Nussenzweig, co-authors of the paper are Rockefeller postdoctoral associate Eric Meffre and Michael Difillppantinio, Jhe Zhu, Hua Tang Chen and Thomas Ried of the National Cancer Institute and Edward E. Max of the Food and Drug Administration. Funding was provided by the National Institutes of Health.

Rockefeller began in 1901 as The Rockefeller Institute for Medical Research, the first U.S. biomedical research center. Rockefeller faculty members have made significant achievements, including the discovery that DNA is the carrier of genetic information and the recent determination of the 3-D structure of the cellular RNA polymerase, a molecular machine that activates individual genes. The university has ties to 20 Nobel laureates, including the recipient of the 1999 Nobel Prize for Physiology or Medicine, Günter Blobel. Thirty-three faculty members are elected members of the U.S. National Academy of Sciences, including the president, Arnold J. Levine, Ph.D.