Discovery of Critical DNA-Repair Enzyme Helps Researchers Understand Alzheimer’s, Aging, Cancer

Using data from the Human Genome Project, researchers have identified a key part of the toolkit human cells use to repair damage to their genetic material, damage that has been implicated in everything from Alzheimer's disease to cancer to the normal aging process.

In a paper published in the March issue of Proceedings of the National Academy of Sciences, researchers describe their discovery and characterization of an enzyme that works to fix errors introduced into human DNA by oxidative stress, one of the most common processes operating on living cells.

Oxidative damage to DNA occurs when the chemical bases that spell out the genetic code are attacked by highly reactive oxygen, substances produced naturally as a byproduct of respiration and also as a result of infection, inflammation, cigarette smoking and alcohol consumption. Unless they are corrected, the resulting changes are then passed along to the cell's descendants, causing a dangerous accumulation of genetic mistakes.

"Oxidative damage is the mother of all damage," says Mitra, a professor in Sealy Center for Molecular Science of the University of Texas Medical Branch at Galveston. "It is the dominant form of stress in aerobic organisms, and we are constantly experiencing it — every time we breathe we are exposed to oxidative stress. So our DNA has to have a repair mechanism."

To better understand how the repair mechanism functions, Mitra and his colleagues decided to find sequences in the human genome database for DNA repair enzymes similar to those identified as glycosylases in the bacteria E. coli.

After identifying two such sequences, the researchers used one of them to produce a previously unknown protein, which proved able to function as a glycosylase when tested on damaged DNA. This glycosylase, which they named NEH1, is the first to be discovered in a new class of mammalian DNA repair enzymes, and it possesses two characteristics that make it seem a particularly important player in the struggle against oxidative damage.

First, unlike the other mammalian glycosylases, NEH1 may work on the small, critical portion of human DNA that is actually active. (Only 3 percent of the total genome carries functional genetic information, and based on current evidence it appears likely that the other DNA glycosylases operate only on inactive DNA.) Second, cells produce far more NEH1 when their DNA is replicating — as if in an effort to catch any errors introduced by oxidative stress before they are passed on to the next generation.

The researchers also examined human tissues for NEH1, seeking to determine its relative level in different organs of the body. They found that messenger RNA coding for NEH1 was highest in the liver, pancreas and thymus.

According to Mitra, the identification of NEH1 is a crucial step toward working out the ways in which oxidative stress produces any number of health problems. "What we are seeing are the subtle nuances of repair," Mitra says. Knowledge of how the DNA repair process works in different people — how it can vary depending on age, genetic heritage and exposure to toxins and pathogens — could be highly useful in understanding individual susceptibility to disease. Understanding how it functions differently in different organs of the body — NEH1's high levels in the liver are especially intriguing, for example — may shed light on disorders of particular human systems.

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