Mayo researchers find off/on switch for DNA repair protein

Volume 7, Issue 4, 2018

Summary

The work provides a new target for developing therapeutics to help kill ovarian cancer cells.

Georges Mer, Ph.D.

Georges Mer, Ph.D.

Damage to DNA is a daily occurrence but one that human cells have evolved to manage. Now, in a paper published in Nature Structural & Molecular Biology, Mayo Clinic researchers have reported how one DNA repair protein gets to the site of DNA damage. The researchers say they hope this discovery will advance new therapies for ovarian cancer.

While the human genome is constantly damaged, cells have proteins that detect and repair the damage. One of those proteins, called 53BP1, is involved in the repair of DNA. In the published paper, Georges Mer, Ph.D., a structural biologist at Mayo Clinic in Rochester, Minnesota, and his team report on how 53BP1 relocates to chromosomes to do its job.

In the absence of DNA damage, 53BP1 is inactive — blocked by a protein called TIRR, Dr. Mer said. Using the visualization technique X-ray crystallography, the authors show that TIRR obstructs an area on 53BP1 that 53BP1 uses to bind chromosomes. But what shifts TIRR away from 53BP1 so the repair protein can work?

The authors theorized that a type of nucleic acid called RNA was responsible for this shift.

To test their theory, they engineered a protein that would bind to the 53BP1 repair protein and the RNA molecules released when DNA is damaged. This effort, plus other work detailed in the paper, provides evidence that their idea is sound. The authors report that when DNA damage occurs, RNA molecules produced at that time can bind to TIRR, displacing it from 53BP1 and allowing 53BP1 to swing into action.

"Our study provides a proof-of-principle mechanism for how RNA molecules can trigger the localization of 53BP1 to DNA damage sites," Dr. Mer said. "The TIRR/RNA pair can be seen as an off/on switch that blocks or triggers 53BP1 relocation to DNA damage sites."

Also in the paper, the authors report that displacing TIRR increases sensitivity of cells in cell culture to olaparib, a drug used to treat patients with ovarian cancer.

"Unfortunately, over time cancer cells develop resistance to drugs in this category, called PARP inhibitors. Our work provides a new target, TIRR, for developing therapeutics that would specifically help kill ovarian cancer cells," Dr. Mer said.

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