Demystifying DNA repair could drive better gene therapies

An integral piece of the process that goes into the repair of DNA has been discovered by scientists at Washington State University (WSU) in Pullman, the institution announced Monday. This information could improve gene therapies for hereditary disease.

Flawed DNA repair function can increase risk of developing a wide range of diseases including cancers such as “children of the moon,” a disorder that renders people unable to step out into the light of day due to UV sensitivity, and several cancers.

Researchers including Michael J. Smerdon, PhD, a WSU regents professor focused on this disease in particular while “unbuckling” the proteins involved in DNA repair. They found that this process, which takes place in chromatin, was essential for DNA repair work to begin.

“Even at a basic fundamental level, I have not lost sight of what you hope this research could ultimately do in terms of human health,” said Smerdon. “One of the treatments under development is targeted gene therapy,” he said. “If a patient has a mutation in a specific gene, it would be a way of giving them a normal copy to try to correct that gene. Though it has been done successfully in some diseases, it is still being investigated in repair deficit cases.”

Smerdon describes how each human cell is subjected to as many as 100,000 DNA injuries on a daily basis. Each injury requires quick and effective repair, which involves RNA polymerase copying genetic details and stopping at every station where protein is required. It unravels the double-stranded DNA and then copies one of them for manufacture. However UV or other damage along the way can create barricades and put the cell at risk of death if it isn’t repaired quickly by transcription-coupled repair, or TCR. This is just a piece of one of the four systems known to repair DNA. Just one little thing out of place could spell disease.

Children of the moon is a hereditary disease also known as xeroderma pigmentosum (XP). Those with the disorder do not have the enzymes required to haul off the damage barricading protein manufacture. These people are exceedingly sensitive to UV light and can only operate comfortably in the dark. It is suggested that fluorescent light is enough to cause skin burn, hence the name. Cancer rates among those with the disorder are 2,000 times higher compared to others.

TCR deficiencies can also cause nerve degeneration, premature aging, non-polyposis colorectal cancer, leukemia and breast cancer.

Smerdon et al worked with yeast and human cells and found two separate steps in normal TCR repair. H2B, a chromatin protein, is essential to the first step and unlocks ubiquitin, a smaller protein, allowing the strand of DNA to loosen.  Further research could lead to gene therapies that target DNA repair deficiencies in this process.

The scientists’ findings were published in the Proceedings of the National Academy of Sciences and the research was bankrolled by the National Institute of Environmental Health Sciences.