News Release

Sunday, August 13, 2006

Mouse Study Finds That Mutant Enzyme is Able to Help Protect DNA From Damage

Research has shown that when DNA damage occurs, a key enzyme — called ataxia telangiectasia mutated protein, or ATM — becomes activated. A new study in mice shows that this enzyme continues to be activated and function normally, even without a chemical modification previously thought to be necessary. This study, which was conducted by scientists at the National Cancer Institute (NCI) and the National Institute on Aging (NIA), both parts of the National Institutes of Health, appears online August 13, 2006, in the journal Nature*.

“Although enzyme mechanisms may differ between humans and mice, gaining a better understanding of DNA damage repair might someday allow us to specifically alter ATM in cancer cells. These alterations could make tumors more sensitive to DNA damage and cell death radiation therapy for cancer,” said senior author André Nussenzweig, Ph.D., senior investigator in NCI’s Experimental Immunology Branch.

ATM is a protein that functions to maintain the stability of DNA. It controls the activity of many proteins in a cell by transferring phosphate chemical groups to these proteins. The addition of phosphate groups is a common mechanism used by cells to turn enzymes on and off.

Radiation and other factors can create double-stranded breaks in DNA, and evidence suggests that ATM becomes activated in response to this DNA damage. ATM’s activation was believed to involve a process called autophosphorylation, in which the enzyme would add a phosphate group to itself and then be released from an inactive state. Subsequently, activated ATM then migrates to sites of DNA damage and phosphorylates other proteins that are necessary for halting the cell cycle and repairing DNA damage.

The cell cycle is a carefully regulated process by which cells proliferate. During the cell cycle, a cell grows and divides to produce two new cells, and then the process starts all over again. Bringing the cell cycle to a standstill after DNA damage occurs allows time for the cell’s machinery to fix the errors before abnormal cells are generated. If the damage cannot be accurately fixed, the cell may commit cellular suicide rather than lose control of growth.

Appropriate cell cycle regulation by ATM and other proteins is necessary to prevent abnormal cell growth, which can lead to cancer. In humans, individuals who inherit a mutation in the gene encoding ATM may develop ataxia-telangiectasia, a rare degenerative disease that causes loss of muscle control, a weakened immune system, and an increased risk of cancer.

Mice engineered to lack the ATM gene are also defective in growth and are predisposed to cancer. Mouse and human cells with non-functional ATM are also more sensitive to radiation. Previous studies suggested that autophosphorylation of the ATM protein is necessary for normal function and control of cell proliferation**. The symptoms that result from a missing ATM gene can be alleviated by providing the mice with a new copy of the gene.

The research reported in Nature, led by Manuela Pellegrini, Ph.D., and Arkady Celeste, Ph.D., of NCI’s Experimental Immunology Branch, shows that addition of a mutant version of the ATM protein (Atm-S1987A) that is unable to autophosphorylate can restore normal function to mice lacking ATM. Mice with the Atm-S1987A mutant protein appear normal and do not have the defects that are observed in mice without ATM.

The researchers attribute the rescue of ATM-deficient mice to the ability of the Atm-S1987A mutant protein to function normally without autophosphorylation. Even when immune cells from Atm-S1987A-rescued mice are treated with radiation, several signs of normal cell cycle inhibition were observed, including decreased rate of DNA synthesis and decreased cell proliferation. This mutant ATM protein also migrated to the site of DNA breaks and phosphorylated other proteins appropriately. None of these indicators of regular function can be detected in immune cells from mice lacking ATM. Therefore, the mutant Atm-S1987A protein exhibits normal phosphorylation activity and is sufficient to trigger an efficient response to radiation.

Since autophosphorylation appears to be nonessential for ATM activation and function, the purpose of this modification is unclear. “Autophosphorylation of ATM may just be accidental, or there may be additional sites of autophosphorylation that compensate” speculated Nussenzweig. “Once ATM is recruited to the double-stranded DNA break, lots of other proteins also relocate to the same site for phosphorylation. The high concentration of enzyme activity might result in unintended autophosphorylation at the site we studied or other sites.” The NIH researchers next will try to abolish all ATM autophosphorylation activity in order to pinpoint exactly which phosphate groups might be necessary and which are dispensable in triggering ATM regulation of the cell cycle after radiation damage.

According to acting NCI Director John Niederhuber, M.D., “Making tumors easier to eradicate at lower doses of radiation, while avoiding significant harm to healthy surrounding tissue, would be a significant step forward in this vital area of research. What we learn today in mice can hopefully be applied to humans in the near future.”

To learn more about Dr. Nussenzweig’s research, go to:

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* Pellegrini M, Celeste A, Difilippantonio S, Guo R, Wang W, Feigenbaum L, Nussenzweig A. Autophosphorylation at Serine 1987 is dispensable for murine Atm activation in vivo. Nature. Online August 13, 2006.

** Bakkenist CJ and Kastan MB. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature. 2003; 421:499-506.