Diet, pollution, and other environmental factors can cause a host of human diseases, ranging from cancer to diabetes to Alzheimer’s. The exact mechanism of how this occurs has not been known until now. Using advanced imaging techniques, researchers have been able to see how DNA polymerase inserts harmful molecules into DNA, which can lead to disease. Samuel Wilson of the National Institute of Environmental Health Sciences (NIEHS) was senior author on the paper, which was published in Nature.
DNA polymerase is an enzyme that is integral for DNA replication by connecting nucleotides into chains. Sometimes these nucleotides become damaged through oxidative stress brought upon by free radicals from radiation or exposure to certain chemicals. Images obtained using time-lapse crystallography showed the molecular reactions step by step as DNA polymerase inserted these nucleotides that carried an extra oxygen atom.
“When one of these oxidized nucleotides is placed into the DNA strand, it can’t pair with the opposing nucleotide as usual, which leaves a gap in the DNA,” Wilson said in a press release. “Until this paper, no one had actually seen how the polymerase did it or understood the downstream implications.”
In addition to seeing these damaged nucleotides getting added into the DNA strand, they were also able to note a very important step in DNA synthesis that was prevented from happening: editing. The nucleotides are normally arranged in a way that one strand perfectly pairs up with the opposite strand, just like a zipper. Any damaged or mismatched nucleotides can typically be repaired, but this study found that oxidative stress resists being edited out. Without excising these damaged nucleotides, the DNA does not connect smoothly. This inhibits DNA production or can lead to breaks in the strand.
“The damaged nucleotide site is akin to a missing plank in a train track,” Wilson added. “When the engine hits it, the train jumps the track, and all of the box cars collide.”
If nucleotides damaged by oxidative stress are able to continue to be integrated into DNA strands, the health of the cell can be affected. When this happens to many cells, diseases are able to set in. While this is not good news for normal, healthy cells, the researchers could use this information to come up with new treatments that could attack the damaged and diseased cells. This could eventually lead to new treatments and therapies.
“One of the characteristics of cancer cells is that they tend to have more oxidative stress than normal cells,” explained lead author Bret Freudenthal. “Cancer cells address the issue by using an enzyme that removes oxidized nucleotides that otherwise would be inserted into the genome by DNA polymerases. Research performed by other groups determined if you inhibit this enzyme, you can preferentially kill cancer cells.”
