Structural Snapshots of Damaged DNA

NIH | DECEMBER 12, 2014

Researchers revealed how nucleotides damaged by oxidative stress become inserted into DNA strands and block DNA Repair mechanisms. The cell death triggered by this process is thought to play a role in many diseases.

DNA forms 2 long strands that wind around each other to form a double helix. The building blocks of the strands are known as nucleotides. Nucleotides are assembled into the strands by machinery that includes the enzyme DNA polymerase.

Nucleotides can be damaged by a chemical process called oxidative stress. Ultraviolet exposure, diet, and chemical compounds in consumer products can cause oxidative stress. When nucleotides are damaged, DNA strands become unstable, which may lead to diseases such as cancer, diabetes and Alzheimer's Disease.

A team led by Dr. Samuel Wilson at NIH’s National Institute of Environmental Health Sciences (NIEHS) set out to determine how DNA polymerase inserts damaged nucleotides when assembling DNA strands. They focused on the commonly oxidized 8-oxo-dGTP which may pair with either cytosine or adenine.

The scientists formed crystal complexes of DNA, polymerase, and oxidized nucleotides. They used time-lapse crystallography to capture snapshots at different time points during assembly.

The technique revealed that 8-oxo-dGTP is inserted opposite cytosine in one conformation and opposite adenine in another. With either pairing, the oxidized nucleotide causes a nick—an opening between the 2 DNA strands. This nick blocks the DNA repair machinery.

Oxidized nucleotides are continually removed by the cell. But when they accumulate, the DNA polymerase adds more of them to the strand. Large numbers of the resulting DNA nicks can be lethal to cells and serve as a jumping off point for the development of disease.

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