Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Removing DNA repair gene causes metabolic syndrome


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:

More articles from Life Sciences:

nachricht International team discovers novel Alzheimer's disease risk gene among Icelanders
24.10.2016 | Baylor College of Medicine

nachricht New bacteria groups, and stunning diversity, discovered underground
24.10.2016 | DOE/Lawrence Berkeley National Laboratory

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

New method increases energy density in lithium batteries

24.10.2016 | Power and Electrical Engineering

International team discovers novel Alzheimer's disease risk gene among Icelanders

24.10.2016 | Life Sciences

New bacteria groups, and stunning diversity, discovered underground

24.10.2016 | Life Sciences

More VideoLinks >>>