Medical genetics

The study find that the a new study sheds light on what happens after DNA damage occurs, and how the body initiates repair. A team of researchers at Baylor University want to determine the series of events that kickstart DNA repair in humans after being expose to the sun’s damaging rays. The breakthrough study; which was publish in the journal Oxford Academic Nucleic Acids Research ; reveals how sunlight-induce DNA damage is recognize by the molecular repair machinery in cells for repair.

After DNA damage occurs

Ultraviolet (UV) light from the sun is a common carcinogen that can damage the DNA (deoxyribonucleic acid); in the body. DNA is important because it carries genetic information and blueprints for cellular functions. When the body fails to repair the DNA; damage induced by UV light; it can lead to mutations, and eventually, cancer. UV light poses a threat on genome integrity by triggering DNA damage; also dubbed as intra-strand crosslink damage.

There are two major lesions, including the cyclobutane pyrimidine dimer (CPD); which is about 70% of the damage and 6-4 photoproduct (6-4PP); which constitutes 30%. What is the cellular DNA repair system (NER)? Nucleotide excision repair (NER) genes are responsible for the repair of DNA damage brought about by exogenous agents, such as UV light; chemicals; and ionizing radiation. The NER proteins recognize DNA damage, remove the error, and repair the DNA strand.

The NER works faster for 6-4PP lesions than on CPD lesions, since the DNA damage-sensing protein known as Rad4/XPC that stimulates NER is more effective at distinguishing 6-4PP lesions. When the Rad4/XPC binds with the lesion, the NER pathway can remove it more efficiently. Though NER works across all organisms, it remained unclear how the DMA damage-sensing protein distinguishes the lesions and the difference in the efficiency of recognizing them.

Repair of DNA damage

To land to the findings of the study, the team of researchers determined a 3D structure of Rad4 protein that is bound to a DNA substrate that contains a 6-4PP lesion. They utilized X-ray crystallography and from there; they saw that the protein flips outward the parts of the DNA that contains the 6-4PP. Hence; it opens the DNA double helix, followed by untwisting and bending the DNA strands.

They also found that the proteins bound not on the damaged parts of the DNA, but instead, on the healthy parts opposite to the lesion. They then computationally stimulated the process wherein the Rad4 may bind with the DNA containing either CPD or 6-4PP. The simulation revealed that the protein readily acts on the 6-4PP to untwist, bend, and partly open the DNA at the site of the lesion. On the other hand, the CPD-containing DNA resisted the untwisting and bending that was readily occurring in 6-4PP.

The researchers put together a 3D molecular trajectory that shows the important steps that occur during the opening of the DNA. “The hallmark of NER is that it repairs a very broad range of DNA damage. That is quite important in terms of how our genomes are protected from environmentally caused DNA damage,” Dr. Jung-Hyun Min; an associate professor of chemistry and biochemistry in Baylor’s College of Arts & Sciences, said in a statement.

Environmentally caused DNA

“While it has been known for many decades that this Rad4/XPC protein can recognize 6-4PP very efficiently; there has been no structure to show how it really binds to the lesion and why the recognition is so efficient compared with lesions such as CPD. Basically, our study nicely fills this missing gap and details what that mechanism must be,” she added.