The Story of ATM

A genetic quality control inspector fixes DNA damage and prevents precancerous cells from dividing.

Everyday, billions of cells in the body are dividing into two, then four, then eight, in a tightly orchestrated dance. Cells grow and make copies of their genetic information, or DNA. Tiny fibers pull duplicate copies of DNA apart and set them in separate regions of the cell. Then a protective envelope called the nucleus forms around each set of DNA and the single cell splits in two. At several points in this process, the cell pauses, waiting for a signal to tell the cell to “stop” or “go.”

A repairman for DNA

Ataxia telangiectasia mutated, or ATM, is protein that helps the cell repair damage to DNA. The protein also prevents cells with damaged DNA from mutating, and spurs cells with dangerous mutations to commit suicide.

One of these signals is a molecule called ataxia telangiectasia mutated, or ATM, and it plays an important role in preventing cancer, acting as a genetic quality control inspector. Changes in the ATM gene can lead to multiple types of cancer, including blood cancers and breast cancer. About 15 percent of cancer tumors show some changes to the base pairs, or letters in the genetic code, that make up the ATM gene.

Scientists first took notice of ATM in 1995, when they discovered that people with an inherited condition called ataxia telangiectasia had nvo altered versions of the ATM gene. People ·with this condition have progressive problems with walking and motor coordination, called ataxia, and up to 40 percent of them will develop cancer.

When researchers delved further, they discovered that the protein made by the ATM gene helps repair DNA. Normally, two strands of DNA are intertwined in a double helix. But radiation from the sun’s rays, certain drugs, and glitches in the DNA copying process can damage DNA, sometimes slicing through both strands of the double helix. One of ATM’s many jobs is to watch vigilantly for this type of double-stranded cut.

When both strands of DNA are broken, a large complex made of many molecules goes to the site of the break, forming a bridge that ATM lands on. When ATM binds to this repair bridge, ATM turns itself “on” by sticking a special chemical tag called a phosphate group onto itself. Once ATM is “on,” it becomes a kind of molecular Swiss-army knife that can add phosphate group tags to many other molecules, turning them “on” as well.

Some of the molecules ATM activates are genetic repairmen that fix the double-stranded DNA break. But ATM does more than that. When cells contain damaged DNA, ATM also activates other chemicals that send the cells into early and permanent retirement, a process called senescence. ATM does this by halting cell division at multiple checkpoints in the process: either just before a cell’s DNA is duplicated or just before a cell begins the process of splitting in two.

And ATM may also protect the body against cells with dangerous mutations, by setting off a chemical cascade that forces a cell to commit suicide. By guarding the genome from damage, ATM plays a powerful role in preventing cancer.

Mutated ATM genes can either prevent the protein from being made at all, or make a less active form of ATM. Most mutations affect the portion of the ATM protein that adds a phosphate group to other molecules.

When ATM is mutated, cells accumulate harmful genetic changes that can lead to cancer

When someone makes an altered version of A Ti,1, due to a mutation in the A Ti,1 gene that produces the protein, the body cannot repair damage to DNA. As a result, genetic mutations can rack up and healthy cells may transform into cancer cells. Sometimes, tumor cells use A T11’s repair mechanism for their own ends. Cancer cells may dial up the production of AT11, so that they can repair the damage caused by chemotherapy. Those tumors are more resistant to treatment. When the body produces a mutated form of ATM, cells cannot repair DNA damage as well, and cells with broken or damaged DNA may be allowed to divide. As a result, cells can rack up many more mutations that eventually lead to cancer.

But the ATM gene may also play another role in cancer by helping tumors protect themselves against cancer drugs. So how is it that ATM can both protect healthy cells from cancer, and protect cancer cells from chemotherapy or radiation?

Chemotherapy and radiation work in part by deliberately damaging genetic material. Though most cells in the body have genetic material, cancer cells are dividing so fast that they have much more, and are therefore more susceptible to these treatments than the body’s healthy cells. (This is also why people lose their hair during chemotherapy and become anemic, because cells that divide more frequently, such as red blood cells and hair cells, are more affected by the drugs.)

But cancer can co-opt ATM’s powerful repair system for its own ends. Some tumor cells produce many copies of the ATM protein. That, in turn, allows cancer cells to repair themselves after chemotherapy or radiation has damaged their DNA.

Mutations to another DNA-repair gene, called TP53, may also affect how cancer responds to chemotherapy.Tumors with mutations in both ATM and TP53 genes have virtually no repair mechanisms, and are very susceptible to chemotherapy as a result. In contrast, cancers with abnormal TP53 genes but normal ATM genes tend to be more resistant to chemotherapy than the reverse.

Changes to the ATM gene are found in some breast cancers and certain types of blood cancers such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Some studies have tied changes to the ATM gene to bladder, brain, colon, and prostate cancers.

Women with the most harmful types of mutations in the ATM gene have a 60 percent lifetime risk of developing breast cancer, though some other types of ATM mutations only slightly raise the risk of cancer. It’s not clear how ATM affects the prognosis for breast cancer once it does occur, though some studies show that the levels of ATM protein vary in different cancer cell types even within the same tumor. Determining which cells contain high levels of ATM could one day help doctors predict how a cancer will progress.

Mutations in the ATM gene also play a role in chronic lymphocytic leukemia (CLL). It typically takes five to 10 years for CLL to progress to a more aggressive stage, and because people are typically in their 70s when first diagnosed, they may not need any treatment. However, people with CLL who have mutations in the ATM gene do often progress to more aggressive cancer in two to three years, requiring more aggressive treatment. However, about one-third of people with point mutations -alterations in a single base pair of DNA – in the ATM gene will not see their cancer enter a more aggressive stage. And for those whose CLL does progress, there are several treatment options such as chemotherapy, radiotherapy, and bone marrow transplants.

Currently, no approved cancer treatments specifically block or target ATM. But many cancer researchers believe drugs called ATM inhibitors could be a powerful strategy to fight a broad range of cancers. That’s because all cancer cells are usually stripped-down versions of healthy cells. While healthy cells may have many ways of repairing themselves, cancer cells rely heavily on just one or two proteins, like ATM.

So doctors hope that inhibitors can stop ATM from working inside tumor cells. That could prevent cancer cells from fixing themselves, and chemotherapy and radiation could do a better job of destroying the cancer cells. Theoretically, an ATM inhibitor drug could be given before a dose of radiation, making cancer cells more vulnerable to the treatment.

One very common ATM inhibitor is something many people consume everyday-caffeine. However, caffeine on its own isn’t useful for cancer patients because it must be given at dangerously high doses before it shows any cancer-fighting effects.

Ways to improve chemotherapy

Though no available treatments target ATM, doctors are developing drugs to block the action of ATM in cancer cells. If these treatments work, they could make cancer cells more sensitive to chemotherapy or radiation.

In animals, a compound called KU-559403, and its derivative, KU-60019, can make tumors much more sensitive to chemotherapy or radiation. However, those compounds must be injected directly into brain tumors in mice, which would be difficult to do in people. And neither of these compounds has been tested in humans.

Other research, still in early development, focuses on a similar DNA repair molecule, called ATR. ATR works to repair genetic material after single strands of DNA have been broken. Scientists are now in the very first stages of human trials, studying the safety of ATR inhibitors given just before radiation in patients with solid tumors. However, doctors don’t yet know whether those treatments will be safe or effective. And it’s not yet clear that these compounds would work for people whose cancers contained a mutation in the ATM gene; more clinical trials will be necessary to explore this.

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