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News

Chemist Tom Tullius finds directional bend to helix, posits role in repair processr

Boston University : 16 April, 2003  (Technical Article)
Fifty years after the discovery of the helical structure of DNA, the body of knowledge on the reactions of that structure to damaging agents such as ionizing radiation now has a valuable addition.
Tom Tullius, professor and chairman of Boston University’s Department of Chemistry, has shown that a type of radiation-induced change, the loss of a single nucleoside in one strand of DNA, bends the helix in only one direction. This anisotropic kink, he postulates, produces structural and dynamic characteristics that DNA repair proteins may use to locate and mend damaged sites. When repaired, DNA can again provide a template from which proteins can be assembled accurately. These findings appear in the April 1, 2003, Proceedings of the National Academy of Sciences, a special issue devoted to research in bioinorganic chemistry.

At the cellular level, x-rays and other forms of ionizing radiation strip atoms from molecules, creating free radicals that disturb cell activity in a number of ways, including damaging DNA. Although this damage can be destructive to DNA, other changes can be repaired by proteins within the cell. One such repairable lesion is the single-nucleoside gap. Tullius chose to investigate the effects this lesion had on DNA’s helical structure.

Tullius and his co-investigator Hong Guo, a former graduate student in Tullius’ group and now with the Connecticut-based firm Photometrix, worked with a DNA fragment that had been designed to have a fixed bend. This bend occurred where the DNA molecule had four sets of five adenine–thymine pairings. The nucleosides adenine and thymine, along with cytosine and guanine, pair up and bond in the DNA helix.

A–T sequences naturally form a bend in DNA, a characteristic that can be identified using gel electrophoresis, an analytic tool used to separate mixtures of electrically charged molecules such as proteins or nucleosides. He and his co-investigator devised a two-dimensional gel electrophoresis technique to investigate structural changes in the DNA fragment, using the A–T bend as a point of reference.

To generate single-nucleoside gaps in the DNA fragment, the researchers duplicated nature’s tool, the free radical. By reacting iron(II) EDTA with hydrogen peroxide, they manufactured hydroxyl radicals, the free radical that forms when ionizing radiation strips a hydrogen atom from a water molecule. Hydroxyl radicals act on DNA by stealing a hydrogen atom from deoxyribose sugars in DNA. Deoxyribose residues link with phosphate groups to form the strand of DNA. The sugar–phosphate–nucleoside structure is called a nucleotide.

Tullius treated the bent DNA molecule with the hydroxyl radical and produced a library of DNA molecules, each with a single gap on one of its strands.

When subjected to the two-dimensional electrophoresis experiment the library of molecules exhibited a highly periodic pattern that remarkably resembled an image of the DNA helix itself. This pattern repeated at approximately every 10.5 nucleotides, the same period found in a DNA helix.

The researchers attributed the periodic pattern to a counter play of fixed bends, that of the reference-bend molecule versus that of molecules with experimentally induced bends. Had the bends caused by the single-nucleoside gaps acted as swivels, they reasoned, the pattern would not show such well-defined periodicity.

The researchers noted that their findings offer additional insight to investigations that indicate a fixed bend at a gap site may act as a signpost to DNA repair proteins that specialize in repairing damage by free radicals.
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