Protein Plays Crucial Role In Repairing Genetic Damage That Can Lead To Lymphomas

Genetic Damage

ATM kinase protein 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