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Removing DNA repair gene causes metabolic syndrome

10.02.2006


OHSU study on mice is first to link disorder with enzyme pathway; may be key to preventing human diseases



Removing a gene involved in repairing damaged DNA causes mice to develop the metabolic syndrome, researchers at Oregon Health & Science University have discovered.

Scientists at OHSU, the University of Texas Medical Branch and the University of Alabama found that generating mice that lack the gene encoding the DNA repair enzyme NEIL1 causes them to develop severe obesity and reach nearly twice the weight of their normal counterparts. The mice, according to the study appearing in the Proceedings of the National Academy of Sciences, also had enlarged, fatty yellow livers, insulin levels four times higher than normal, elevated levels of fat cell byproducts, and many internal organs almost entirely encased in thick pads of fatty tissue.


The results are the first to link DNA repair with the metabolic syndrome, and they suggest an important role for the NEIL1 gene product in the prevention of the diseases associated with the disorder, including obesity, hypertension, high cholesterol, insulin resistance and kidney disease.

"So if there are catalytically compromised forms of NEIL1 within the U.S. population, these people will be predicted to be at increased risk for developing the metabolic syndrome," a disease believed to affect more than 40 million Americans, said R. Stephen Lloyd, Ph.D., senior scientist at OHSU’s Center for Research on Occupational and Environmental Toxicology (CROET) and co-author of the study.

Lloyd and his colleagues originally discovered the NEIL1-deficient mouse’s propensity for developing the metabolic disorder about two years ago. Their interest in NEIL1 was initiated by their efforts to clone and crystallize homologs to the Escherichia coli endonuclease VIII gene. E. coli endonuclease VIII is part of a pathway of enzymes involved in repairing DNA damaged by free radicals that trigger oxidative stress on cell molecules. As a consequence of these studies, the Lloyd laboratory found human homologs to the bacterial repair enzyme and immediately began constructing the repair-deficient mice.

"If you have oxidative stress inside the cell, then the bases in the DNA can become damaged, and the responsibility of this whole group of enzymes is essentially to monitor the entire genome, looking for genomic bases that have been oxidatively damaged," Lloyd explained. "They have the responsibility of then removing the damaged bases, which initiates a process by which the cell puts in a normal piece of DNA where the damaged DNA was. This happens every second of your life."

After breeding several generations of NEIL1 "knock-out" mice, Lloyd’s colleague and the study’s lead author, Vladimir Vartanian, Ph.D., found that the mice lacking the enzyme reached weights of between 45 and 52 grams at age 7 months, while normal mice weighed in at only 28 grams. They also were extremely lethargic, their hair was turning gray, and some were even going bald.

And there were gender differences. "The NEIL1 knock-out males throughout all of our studies usually show a more severe form of the disease and earlier onset of the disease than the females. We have consistently seen this," Lloyd said. "The female has disease, but it’s not nearly to the same severity."

Previous studies have suggested that because there are increased levels of NEIL1 during the synthesis or "S" phase of the cell division cycle, during which DNA is replicated before the cell actually divides, NEIL1 is important to replication-associated DNA repair. In addition, NEIL1 has been shown to be localized in both the cell’s nucleus and its power plant, the mitochondria, pointing to its likely involvement in the overall maintenance of the genome’s stability. Other investigators in the field have discovered that NEIL1 may be important in the repair of actively transcribed genes.

This means mutations in the NEIL1 gene, or the gene’s absence altogether, could have a catastrophic effect on the body’s ability to restore DNA to its undamaged state.

"Our analysis is that the inability to repair damage to the genetic material, whether it is in the nucleus or whether it’s in the mitochondria, is what’s leading to a destabilization of a normal metabolic process," Lloyd said. "That then begins to cascade and ultimately results in the symptoms that are consistent with the metabolic syndrome."

Lloyd says he hopes to study individuals suffering from the metabolic syndrome with the goal of someday developing a genetic screen for the disease. He also wants to examine ways to delay the onset of symptoms, such as increasing the expression of the NEIL1 gene or dampening oxidative stress to the cells that damages their DNA. Such techniques could one day become therapies.

"One may be able to develop a diagnostic method to do early screening," Lloyd said. "Or there could be a drug discovery mechanism in which you enhance the transcription process (of NEIL1) and just make more. Maybe you only have one good copy. Fine. Maybe we can upregulate that one."

More importantly, "What we think this publication is going to do is add one more complexity to the potential mechanisms by which you could get to disease," he said.

Jonathan Modie | EurekAlert!
Further information:
http://www.ohsu.edu

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