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Chemically fingerprinting DNA damage.

Chemically fingerprinting DNA damage

Researchers have accomplished the first precise structural identification of chemical changes that occur when a foreign substance chemically binds to DNA. These changes, known as adducts, are widely suspected as a primary instigator of many cancers. While scientists in the past rounded up and counted suspect adducts, this is the first time anyone has "fingerprinted" individual suspects for an unambiguous chemical identification.

Carcinogens can generate an array of different adducts. Miral Dizdaroglu and his colleagues, working at the National Institute of Standards and Technology in Gaithersburg, Md., focused on a type known as DNA-protein crosslinks.

DNA naturally wraps around protein in nucleosomes, a chromosome's smallest unit. The researchers took pairings of this DNA and protein, and exposed them to an intense dose of hydroxyl radicals -- chemically reactive water-molecule fragments. In both the DNA and the protein, the hydroxyl radicals spawned new radicals, or reactive molecular fragments containing an unpaired electron. Seeking to find mates for their unpaired electrons, these linked up with adjacent biological material, yielding more than a dozen species of DNA-protein crosslinks.

Though Dizdaroglu generated his hydroxyl radicals by exposing water to gamma rays, radiation is but one of many carcinogens suspected of causing biological damage through free radicals, such as the hydroxyl radical. For this reason, Dizdaroglu believes his free-radical-induced changes simulate those wrought by many toxic agents.

Using a combination of gas chromatography and mass spectrometry, the research team separeted different types of adducts and identified their chemical structure. The results, reported in Seattle last week at the annual meeting of the Radiation Research Society, showed that both of the DNA bases studied -- thymine and cytosine -- readily transform to adducts, as do most of the protein's amino acids. Dizdaroglu is now looking to see if the same adducts occur in living cells damaged by hydroxyl radicals.

"This is a real breakthrough," comments biochemist Nancy Oleinick, who studies radiation-generated DNA damage at Case Western Reserve University in Cleveland. Radiation creates a broad spectrum of damage, including adducts. Because no one adduct tends to occur in large numbers, she says, researchers seeking them have been limited to "characterizing the sequences of DNA and the types of proteins that are involved in forming these adducts" -- essentially identifying the general communities of chemicals available to interact. Now, she says, Dizdaroglu has been able "to unequivocally identify individual chemical species." Moreover, his data show that the DNA-protein adducts form by covalently crosslinking -- something scientists had inferred but never directly demonstrated before, says Anne Cress of the Arizona Cancer Center in Tucson.

Researchers can now begin developing DNA probes to seek and count specific adducts -- even to scout for adducts within individual genes, thereby determining which of the genes, if any, are targeted or are especially susceptible to injury by particular toxic agents, Cress says. The new findings also hold out hope that scientists will be better able to correlate toxic-substance exposures to the diseases they cause by analyzing how well the body repairs the newly identified adducts.

For all these reasons, Cress believes Dizdaroglu "has really given us an important new tool."
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Author:Raloff, Janet
Publication:Science News
Date:Apr 1, 1989
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