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VU ‘crosslinks’ study sheds light on chemical toxicity

Oct. 31, 2013, 10:25 AM

Vanderbilt University researchers have characterized the chemical structures of a series of DNA-protein “crosslinks” that may lead to better ways to avoid the cancer-causing potential of environmental chemicals and prevent some drug toxicities.

“We’ve learned the details of how a protein gets attached to DNA to cause damage,” said F. Peter (Fred) Guengerich, Ph.D., senior author of a report published in October as a “Very Important Paper” in the German journal Angewandte Chemie.

F. Peter (Fred) Guengerich, Ph.D.

“That doesn’t tell us all the biological events,” said Guengerich, the Tadashi Inagami Professor of Biochemistry and former director of the Vanderbilt Center in Molecular Toxicology, “but at least it gives us a blueprint to work from.”

The research, led by former Vanderbilt post-doctoral fellows Goutam Chowdhury, Ph.D., and Sung-Hee Cho, Ph.D., focused on ethylene dibromide, a pesticide and gasoline additive that was pulled from the market in the late 1970s when it was found to be a carcinogen.

The cancer-causing potential of this chemical is enhanced by an enzyme called O6-alkyguanine-DNA alkyltransferase (AGT), which normally repairs DNA damage.

Aided by longtime Guengerich collaborator Anthony Pegg, Ph.D., professor emeritus at Penn State, the researchers were able to detect and characterize crosslinks formed between DNA, ethylene and AGT.

“There are many chemicals, including some drugs, that cause protein-DNA crosslinking,” Guengerich explained. “We think that by better understanding this, we can prevent some of the toxicity associated with some of (them).”

Guengerich said it took a decades-old technique known as the Raney nickel procedure to break down the cross links, which were then analyzed in the Mass Spectrometry Facility Core, part of the Center in Molecular Toxicology.

“The mass spec was absolutely critical for doing this type of work,” he said.

The research was supported by National Institutes of Health grants ES010546 and ES000267.

Postdoctoral research fellow Matthew Windsor, Ph.D., contributed to this story.

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