NIH And Rockefeller Researchers Find That Gene Acts As "Caretaker"
Nussenzweig M.D., Ph.D.
Researchers at the National Institutes of Health and Rockefeller
University have found that a gene known for repairing breaks in
the double strands of DNA also acts as a "caretaker" that prevents
chromosome segments from rearranging. Recognizing this additional
role for the gene, called Ku80, could increase ways of targeting
some tumors that develop when the gene is mutated.
"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
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
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 p53s
normal function is associated with an estimated 60 percent of
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
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 bodys 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
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
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-two faculty members are elected members of the U.S. National
Academy of Sciences, including the president, Arnold J. Levine,