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Thursday, June 28, 2007
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 disease.
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 for translocations.”
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 from dividing.”
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. Niederhuber, M.D.
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 of cancer.
For more information about cancer, please visit the NCI website at http://www.cancer.gov, or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
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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.