NIH scientists determine how environment contributes to several human diseases

Using a new imaging technique, National Institutes of Health (NIH) researchers have found that the biological machinery that builds DNA can insert molecules into the DNA strand that are damaged as a result of environmental exposures. These damaged molecules trigger cell death that produces some human diseases, according to the researchers. The findings were published recently in the journal Nature and provide a possible explanation for how one type of DNA damage may lead to cancer, diabetes, hypertension, cardiovascular and lung disease, and Alzheimer’s disease.

Time-lapse crystallography, a technique that takes snapshots of biochemical reactions occurring in cells, was used by the researchers to determine that DNA polymerase, the enzyme responsible for assembling the nucleotides or building blocks of DNA, incorporates nucleotides with a specific kind of damage into the DNA strand.

Samuel Wilson, MD, senior researcher, explains that the damage is caused by oxidative stress, or the generation of free oxygen molecules, in response to environmental factors, such as ultraviolet exposure, diet, and chemical compounds in paints, plastics, and other consumer products. He says that scientists suspected that the DNA polymerase was inserting nucleotides that were damaged by carrying an additional 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 says. “Until this paper, no one had actually seen how the polymerase did it or understood the downstream implications.”

Wilson and his colleagues saw the process in real time, by forming crystal complexes made of DNA, polymerase, and oxidized nucleotides, and capturing snapshots at different time points through time-lapse crystallography. The procedure not only uncovered the stages of nucleotide insertion but indicated that the new DNA stopped the DNA repair machinery from sealing the gap. This fissure in the DNA prevented further DNA repair and replication, or caused an immediate double-strand break. Read the article preview.