Most folks nowadays know that the acronym ATM denotes "automatic teller machine" - the banking convenience that dishes out money and takes in deposits at the tweak of a keyboard.

For immunologists, oncologists and hematologists, the sinister ATM initials stand for "ataxia-telangiectasia" (A-T) - a rare, inherited, fatal whole-body catastrophe. "Between 500 and 1,000 children in the U.S. have this disease," observed Michael Kastan, who chairs the Department of Hematology-Oncology at St. Jude Children's Research Hospital in Memphis, Tenn.

In this somber context, the ATM gene stands for "ataxia-telangiectasia mutated." It resides on the long arm of human chromosome 11. The protein product that gene expresses is the ATM enzyme.

"ATM is present in every person, and in every cell of their body," Kastan pointed out, "and it helps all cells respond to them. A-T's inheritance pattern," Kastan continued, "is autosomal recessive. That means both parents must be carriers of the mutant genes in order for their child to have the disease. There appear to be many different mutations, so it's not just one that causes the affliction. The mutated genes act as a master regulator of cellular responses to DNA double-strand breaks."

Typically, the mayhem wreaked on the damaged DNA consists of breaking its double strands, caused by exposure to ionizing or ultraviolet radiation, environmental toxins or oxygen-free radicals. Among the many types of damage that arise in DNA, the deadliest are double-strand breaks, where both phosphate backbones of the double helix are severed. Such DNA breaks are not unusual in healthy people. They are a necessary step in the embryonic formation of sperm and ova, as well as immune system lymphocytes - B and T cells.

"Patients who lack the enzyme suffer a number of physical and neurological abnormalities," Kastan went on. That understatement runs the gamut from slow degeneration of the brain's cerebellum to a spectrum of immune system deficiencies, staggering gait, widespread skin lesions, sterility, an exquisite sensitivity to ionizing radiation - notably exposure to X-rays - and a pronounced proneness to cancer. By age 10, a child born with A-T is likely to be wheelchair bound. Death intervenes in the 20s to 30s.

Kastan is senior author of an article in today's issue of Nature, dated Jan. 30, 2003. Its title reads: "DNA damage activates ATM through intermolecular autophosphorylation and dimer association."

It Takes A Phosphokinase Every Time

"The mechanistic role of phosphorylation in this context," Kastan told BioWorld Today, "is that it causes the ATM dimer protein to dissociate. The ATM exists as a dimer in the cell - one ATM molecule bound to another. That tightly paired binding keeps other substrates from getting to the phosphokinase domain. So the enzyme can't phosphorylate other proteins because it's bound to a dimer partner. That phosphorylation pushes those molecules apart, and now the ATM is free to roam about the cells and phosphorylate substrate. That's the unique mechanism of enzyme regulation we report here," he added.

The co-authors found that ATM is activated by a signal from damaged DNA only seconds after the adverse event occurs. The activated ATM, in turn, energizes other proteins by attaching the phosphate molecule to them. This sets off a cascade of biochemical reactions that amplifies the initial ATM response. "Among the proteins we discovered phosphorylated by ATM," Kastan said, "are two tumor-suppressing oncogenes, BRCA1 and p53. These molecules play important roles in preventing cancer, while their mutated forms are responsible for inherited malignancies.

"Our findings," Kastan pointed out, "could lead to new approaches to prevent cancer, better ways to treat cancer and to the development of sensitive methods determining whether people have been exposed to such toxic stresses. This critical first step - a chemical modification of the ATM enzyme - allows that protein to initiate a series of events that ultimately halt the growth of the DNA-maimed cell and help it to repair and survive.

"This finding is important," Kastan added, "because DNA damage caused by radiation and environmental toxins can lead to mutations or cell death, and the development of cancers. We have constructed two antibodies," he recounted. "One - a phospho-specific antibody - recognizes ATM only when it's phosphorylated, and therefore identifies only those ATM molecules that are responding to damaged DNA. Our technique for identifying activated ATM is so sensitive that we've been able to show that it takes only a couple of breaks in the entire DNA of the cell to activate and initiate all of its response mechanisms. These antibodies may provide a very sensitive way to determine if cells in a person have been exposed to an agent or toxin that damages DNA. Such an assay has many obvious potential uses - including the assessment of exposure to dangerous agents in the environment. The other antibody recognizes ATM only when it's inactive - not phosphorylated."

Wanted: Therapeutic Drugs That Inhibit 2 Ways

"This work will, hopefully, allow us now to develop agents that either inhibit ATM activation or sensitize tumors to radiation, which is a particular interest of ours as a therapeutic tool. On the flip side, the potential exists that by enhancing activation of ATM we could make cells more resistant to damage, which perhaps could help protect people from radiation toxicity, and even help prevent cancer. So we're exploring those therapeutic implications as well.

"Now in our ongoing research we're also exploring how a DNA break affects chromatin structure - the general nuclear architecture in the cell. We're trying to figure out how ATM is attached to various nuclear structures and senses the break even when it's very far away. A second area of great interest is to better understand the protein structure of ATM. So we're hoping that by X-ray crystalograph we'll get a crystal structure that would help us design drugs, both that inhibit or activate the enzyme in radiosensitizing tumors, and in potential use for radio protection and cancer prevention.

"A patent application has been submitted," Kastan concluded.