New research from the National Institute of Environmental Health Sciences has identified for the first time how damaged molecules become inserted into the DNA strand. These molecules may contribute to some diseases – such as cancer, diabetes, hypertension, cardiovascular and lung disease – as they trigger cell death.
Image credit: NIEHS
Publishing their findings in the journal Nature, researchers from the National Institute of Environmental Health Sciences (NIEHS) describe how they used a technique called time-lapse crystallography to take snapshots of biochemical reactions happening within cells.
With this technique, the researchers were able to observe for the first time how DNA polymerase – the enzyme that assembles the building blocks of DNA, known as nucleotides – weaves nucleotides into the DNA strand.
They also witnessed how, when damaged DNA is inserted into the strand, it creates a fissure that the usual DNA repair mechanisms are unable to repair.
“The damaged nucleotide site is akin to a missing plank in a train track,” says Dr. Samuel Wilson, senior researcher on the team. “When the engine hits it, the train jumps the track and all of the box cars collide.”
The damage to the nucleotide, Dr. Wilson says, is caused by “oxidative stress.” This is the generation of free oxygen molecules as a response to exposure to certain chemicals, ultraviolet exposure or other environmental factors.
Nucleotides become “oxidized” when they carry an extra oxygen atom. Oxidized nucleotides are usually kept tightly under control, but if they begin to outnumber undamaged nucleotides, the DNA polymerase adds them to the strand.
Dr. Wilson explains:
“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. Until this paper, no one had actually seen how the polymerase did it or understood the downstream implications.”
The team also suggests that antioxidants – molecules that prevent oxidation – may reduce the level of the oxidized nucleotides, preventing potential disease.
Although the breaks in the DNA strand caused by these oxidized nucleotides can spur on the development of disease by killing cells, the researchers suggest a potential benefit may be found in controlling the process to kill cancer cells.
Cancer cells tend to have more oxidative stress than normal cells, explains Bret Freudenthal, PhD, lead author of the paper:
“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.”
Recently, Medical News Today reported on a study published in the journal Cancer Research that examined whether DNA “blind spots” – repetitive regions of the strand that cause a “stutter” in the machinery – might conceal cancer genes.
Other recent research has investigated how cells copy their chromosomes – tightly packed bundles of DNA – when they divide. This copying is an important element of cancer research, as it is when mistakes are made in the chromosome-copying process that cells behave abnormally and trigger cancer.