New Substance Identifies Disease-Causing Agents
Enzyme targets and removes DNA damage
FRIDAY, March 22, 2002 (HealthDayNews) -- An enzyme that senses and chops off damaged DNA may play a crucial role in how the body repairs genetic errors caused by harmful oxygen radicals.
The authors of a new study that identifies the enzyme say that the finding, which sheds light on the body's response to oxidative damage, could offer clues to aging and diseases linked to oxygen radicals.
"We produce reactive oxygen radicals all the time, [including] as byproducts of respiration and any time we have an infection or inflammation," says the study's senior investigator, Sankar Mitra, a professor of human biological chemistry and genetics at the University of Texas Medical Branch, in Galveston. "The radicals are responsible for a variety of diseases -- cancer, arthritis, heart disease, Alzheimer's and other sorts of neurological degenerative disease--" as well as aging.
"Free radicals react with everything in the body, obviously, but our primary interest is the reaction with DNA, our genetic material," he says, adding that the reactions at this level ultimately give rise to disease.
DNA, the genetic blueprint for living organisms, is arranged like a coiled ladder. Each rung is made of two molecules, called bases, which pair in an orderly way. But errors can creep into this system, especially as a result of damaging oxygen radicals. And that's where a repair system becomes critical.
In his study, Mitra and his colleagues looked for mammalian genes with similarities to a DNA repair enzyme found in the E.coli bacterium. Armed with data from the Human Genome Project, the researchers identified several candidate genes and finally pared their search down to a gene that they named NEH1.
"If some sort of damage is produced in a cell, it puts the damage in the DNA," says Mitra. "This class of enzyme actually removes the piece that's damaged. It recognizes the damage, binds to it and then cleaves it off."
After that, secondary mechanisms step into the repair the damage at the site.
Exactly how NEH1 knows when damage has occurred, and where, is still not clear, but Mitra's team has a theory.
"We believe that once the DNA damage is produced, and once the enzyme recognizes this site, then it recruits several other proteins," says Mitra. The enzyme binds to these proteins, which may already be at the site of the damage.
According to Mitra, it's possible that NEH1 specializes in damage to the three percent of the genome that carries functional genetic information.
"In the body, we have a huge excess of DNA which has apparently no function," he says, and that remaining 97 percent made up of inactive DNA may be serviced by other repair enzymes.
The researchers were also fascinated to discover that cells produce far more of the enzyme when replication is happening when errors are most likely. "During replication, the level of the enzyme goes up significantly," says Mitra. "It could be as much as five- or ten-fold [higher]."
The researchers also examined human tissue types and found that the highest levels of NEH1 were present in the liver, pancreas and thymus, but it's not clear why levels peak in these particular tissue types.
Dr. Samuel Wilson, the deputy director of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., says the findings are a "landmark study."
"It describes a new type of DNA repair enzyme that protects the genome from damage," says Wilson. "It tells us that there are likely to be many more enzymes in this class or category than we had realized previously. That concept is very exciting for researchers in the field."
"It could have implications for more precise drug design to enhance DNA repair," he says. Paradoxically, he says, blocking the enzyme and its cell repair role could allow other cell tactics for bypassing damage to flourish. "Strategies to prevent DNA repair and allow lesion bypass to occur might be important drug approach strategies."
The research team is now investigating two other potential DNA repair genes, and they are creating a strain of mice genetically altered to lack the NEH1 gene, which should provide a clearer indication of the enzyme's function.
They also plan to study the actions of the enzyme during development, when cell replication is occurring on a grander scale. Mitra says he expects to see higher levels of the enzyme during development.
"We need to look at the level of this protein in a variety of disease states, like in cancer cells," says Mitra. "If the cancer cells do express a high level of this protein because cancer cells are trying to resist chemotherapy, then it's a possibility that [targeting this gene] could be one way of reducing the development of resistance."
The findings appear in this week's issue of the Proceedings of the National Academy of Sciences.
What To Do
Find out about the Human Genome Project from the National Human Genome Research Institute.