DNA damage caused by cancer treatment reversed by ZATT protein

An international team led by scientists at the National Institutes of Health is the first to discover a new way that cells fix an important and dangerous type of DNA damage known as a DNA-protein crosslink (DPC). The researchers found that a protein named ZATT can eliminate DPCs with the help of another protein, TDP2. Since DPCs form when individuals receive some types of cancer treatments, understanding how TDP2 and ZATT work together to repair the damage may improve the health outcomes of cancer patients.

Illustration of a TOP2 DNA-protein cross-link (magenta) bound to DNA. Image credit: Scott Williams/National Institute of Environmental Health Sciences

Researchers knew that TDP2 was important for removing DPCs, but they did not know how it was directed to where it needed to work. The team used a multi-pronged approach to identify ZATT as a new contributor to this process and determine how it guides TDP2 to DPCs so they can be repaired.

To visualize how these proteins choreograph DPC repair, one must first know how DPCs are created. When DNA becomes tangled inside of cells, organisms use a protein called topoisomerase 2 (TOP2) to untangle it.

TOP2 normally conceals its cut DNA ends within the core of the TOP2 protein that encircles DNA. Doing so ensures the protein can complete the second part of its job, which is rejoining DNA ends.

However, chemotherapeutic drugs or environmental chemicals sometimes block the protein’s DNA-retying ability, so that TOP2 remains stuck on DNA. This situation creates a stable TOP2-DPC complex, which leads to the accumulation of severed DNA that kills cells.

They likened TOP2-DPCs to ticking time bombs for cells. He said these molecular charges are armed by TOP2’s interaction with environmental toxicants, chemical metabolites, tobacco exposures, or DNA damage caused by ultraviolet light.

TOP2-DPCs are most potently formed by pharmaceutical drugs that humans exploit to eradicate cancer cells, making TOP2-DPCs double-edged swords. If they are not removed, they trigger cell death. While cancer drugs induce formation of TOP2-DPCs to treat cancer, TOP2-DPC lesions can also be the source of disease, as they can cause rearrangement of an organism’s genome that leads to cancer.

Chemotherapeutic drugs, such as etoposide, are not the only pharmaceuticals that induce DPCs. Many of the antibiotics that are currently on the market use the same method to damage bacterial DNA. (National Institutes of Health)

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