|Protein Plays Crucial Role in Repairing Genetic
Damage that Can Lead to Lymphomas in Mice
Researchers have discovered that a protein called ATM kinase,
which plays a crucial role in repairing double-strand breaks in
DNA, also helps prevent cells with this type of DNA damage from
dividing, thereby blocking the passage of persistent DNA damage
on to daughter cells. Persistent DNA damage can lead to the development
of cancer. These results, from a study conducted in mice by scientists
at the National Cancer Institute (NCI), part of the National Institutes
of Health, and others appeared online June 28, 2007 in the journal Cell and
will be published in the July 13, 2007 issue of the journal.
Andre Nussenzweig, Ph.D. of NCI's Experimental Immunology Branch
in the Center for Cancer Research, teamed with his brother, Michel
Nussenzweig, M.D., Ph.D., Laboratory of Molecular Immunology of
Rockefeller University and a Howard Hughes Institute medical investigator,
and others, to investigate the role of ATM in maintaining genome
stability. “These breaks are particularly dangerous because they
can interact with other DNA breaks in the cell, or in a daughter
cell, which can lead to a translocation of genes,” said Andre Nussenzweig.
A translocation is the inappropriate joining of two DNA segments
that normally are not connected. “In lymphocytes, which are a type
of white blood cell, such a translocation might activate a cancer-promoting
gene and become one of the first steps in the formation of a lymphoma.” Lymphomas
are cancers of the lymphatic system, which is a major part of the
immune system. Lymphomas will be diagnosed in an estimated 71,380
Americans in 2007 and 19,730 people are expected to die of the
The DNA in cells can be damaged or broken by external agents,
such as radiation, or inadvertently during the DNA replication
process that is part of cell division. In lymphocytes, DNA breakage
and rejoining also occurs to create the many different types of
antibody and cell receptor genes needed by the immune system to
recognize and destroy foreign viral, bacterial, or parasitic invaders,
or damaged cells, such as tumor cells.
“DNA breakage and joining events in lymphocytes are essential
for building up the diverse repertoire of immune responses in humans
and other animals,” explained Andre Nussenzweig. “On the other
hand, this process is fundamentally dangerous because it generates
DNA double-strand break intermediates, which are potent elements
ATM, or ataxia-telangiectasia mutated kinase, acts as a kind of
caretaker for maintaining the stability of the genetic system. “ATM
basically has two roles,” Andre Nussenzweig said. “First, it helps
to repair the double-strand breaks and, secondly, in the event
the genetic breaks aren’t repaired, ATM prevents the damaged cells
Previous research by Andre Nussenzweig and others has identified
the roles of several genes, and another protein similar to ATM,
in the genetic pathways for repairing double-strand DNA breaks. “The
surprising finding of our study was that, if you eliminate one
of these factors — the ATM kinase — this allows the
cells to divide in the presence of double-strand breaks in the
DNA,” he noted. “It was thought that the other repair pathways
would kick in, even in the absence of ATM, to arrest the cell cycle
progression of damaged cells.”
Most of the experiments in this study involved lymphocytes from
mice that were specially bred to lack ATM function. The scientists
were able to confirm their initial findings in ATM-deficient mice
by treating cells from normal mice with a small-molecule that inhibits
ATM activity. “We found very similar, persistent DNA breaks,” said
Nussenzweig. “When we washed out the drug, we also found that the
damaged cells were eliminated because of the restored ATM activity.
Thus, the cancer promoting genetic instability could be blocked.” In
the absence of ATM kinase, however, the scientists noted that DNA
breaks can persist in peripheral lymphocytes for at least two weeks.
“Because ATM is known to be defective in the rare childhood neurodegenerative
genetic disease called ataxia telangiectasia, which is also associated
with increased risks for lymphocytic leukemia and lymphoma, this
basic research holds the promise of having an important impact
in the clinic in the years to come,” said NCI Director John E.
The researchers plan to explore several questions raised by the
current study: why the other genetic repair pathways were not triggered,
in the absence of ATM, to respond to the DNA damage; how long cells
can survive with unrepaired double-strand breaks; and can they
can discover other examples of persistent genomic damage, where
the initial break generated very early on recombines with another
break in a daughter cell, leading potentially to an increased risk
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at http://www.cancer.gov, or
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Callén E, Jankovic M, Difilippantonio S, Daniel JA, Chen HT,
Celeste A, Pellegrini M, et al. ATM prevents the persistence
and propagation of chromosome breaks in lympyhocytes. Cell,
online June 28, 2007.