Finding that 1-in-a-billion that could lead to disease

August 19, 2007

Errors in the genetic code can give rise to cancer and a host of other diseases, but finding these errors can be more difficult than looking for the proverbial needle in the haystack. Now, scientists at Johns Hopkins have uncovered how the tiny protein-machines in cells tasked to search for such potentially life-threatening genetic damage actually recognize DNA errors.

Appearing online next week in Nature, the Hopkins team describes how the UDG enzyme (for uracil DNA glycosylase) scrutinizes the shape of DNA building blocks by holding onto them and testing their fit into a specially sized pocket. The UDG pocket holds onto mistakes only — the enzyme loses its grip on the right building blocks, which fall back in line with the rest of the DNA.

“Locating damage in DNA is critical for a cell’s survival: So much can go wrong if damage goes unrepaired; cells can’t tolerate any of this going on,” says study author James Stivers, Ph.D., professor of pharmacology and molecular sciences at Hopkins. “But the question is how these enzymes find the few mistakes among the billions of correct building blocks in DNA.”

One typical error that occurs is to the DNA building block cytosine, being chemically converted to a similar-looking building block not normally found in DNA: uracil. “Even water can cause DNA damage,” says Stivers. “It’s not a fast reaction, but water does convert the occasional cytosine into an unwanted uracil.”

To figure out how the enzyme responsible for cutting unwanted uracils out of DNA works, Stivers and colleagues studied a tiny segment of DNA. The research team then asked whether the “breathing” properties of DNA played a role in the search process of UDG. “Although the bases in the DNA double helix resemble the rungs of a ladder, the rungs are not that sturdy,” says Stivers. “They actually pop in and out of the helix a bit, randomly.”

Each time a base pops out of the helix, it exposes itself to water. Thus, using a special chemical trick, the team magnetically labeled water, which allowed them to follow the interaction of water with bases that had randomly popped out of the DNA helix. The researchers could then follow which bases pop out, and for how long, using a strong magnet.

After studying DNA breathing by itself, the researchers then added UDG into the mix. They saw that UDG holds onto the normal DNA building block thymine (T) after it pops out of the DNA on its own. However, because T is not identical to U, UDG then lets it fall back into DNA helix.

When the DNA contains an unwanted U, the UDG enzyme actually grabs on and pulls it all the way out and holds it in the enzyme’s pocket. Once sitting in this pocket, the enzyme clips out the U, leaving a gap in the DNA for other repair machinery to fill in with the correct building block.

“This is the first time we’ve been able to actually see how an enzyme discriminates between right and wrong bases in DNA,” says Stivers. “Our discovery helps us appreciate what properties of DNA itself might lead to errors that are not repaired. “The finding may help address how and where diseases like cancer arise in the genome.”

Source: Johns Hopkins Medical Institutions

Related Stories

Recommended for you

Scientists produce human intestinal lining that re-creates living tissue inside organ-chip

February 16, 2018
Investigators have demonstrated how cells of a human intestinal lining created outside an individual's body mirror living tissue when placed inside microengineered Intestine-Chips, opening the door to personalized testing ...

Data wave hits health care

February 16, 2018
Technology used by Facebook, Google and Amazon to turn spoken language into text, recognize faces and target advertising could help doctors fight one of the deadliest infections in American hospitals.

Researcher explains how statistics, neuroscience improve anesthesiology

February 16, 2018
It's intuitive that anesthesia operates in the brain, but the standard protocol among anesthesiologists when monitoring and dosing patients during surgery is to rely on indirect signs of arousal like movement, and changes ...

Team reports progress in pursuit of sickle cell cure

February 16, 2018
Scientists have successfully used gene editing to repair 20 to 40 percent of stem and progenitor cells taken from the peripheral blood of patients with sickle cell disease, according to Rice University bioengineer Gang Bao.

Appetite-controlling molecule could prevent 'rebound' weight gain after dieting

February 15, 2018
Scientists have revealed how mice control their appetite when under stress such as cold temperatures and starvation, according to a new study by Monash University and St Vincent's Institute in Melbourne. The results shed ...

First study of radiation exposure in human gut Organ Chip device offers hope for better radioprotective drugs

February 14, 2018
Chernobyl. Three Mile Island. Fukushima. Accidents at nuclear power plants can potentially cause massive destruction and expose workers and civilians to dangerous levels of radiation that lead to cancerous genetic mutations ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.