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‘Untangling’ DNA Damage

Instead of killing cancer cells, some treatment methods are breaking down DNA proteins and creating more damage.


 

“Imagine your DNA is a giant ball of yarn,” says Matthew Schellenberg, PhD. That is the metaphor he uses to help describe the findings of a study he conducted with other researchers from the NIH. They discovered how 2 proteins work together to “untangle” DNA damage known as a DNA-protein crosslink (DPC).

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When DNA becomes tangled inside of cells, organisms use another protein called topoisomerase 2 (TOP2) to straighten things out, by cutting and “retying” individual threads. To do that, it first conceals the cut DNA ends within the core of the TOP2 protein, which allows it to then retie, or rejoin, the DNA ends. However, cancer drugs or environmental chemicals sometimes can block this retying ability, so the TOP2 remains stuck. That creates a stable environment for TOP2 and DPC, leading to an accumulation of severed DNA that kills cells.

Scott Williams, PhD, deputy chief of the Genome Integrity and Structural Biology Laboratory at the National Institute of Environmental Health Sciences, headed the team that identified ZATT as a new contributor to the process of removing DPCs. He uses another metaphor, likening the TOP2-DPCs to “ticking time bombs for cells.” The molecular charges are armed, Williams says, by TOP2’s interaction with environmental toxicants, chemical metabolites, tobacco exposures, or DNA damage caused by ultraviolet light.

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While cancer drugs induce formation of TOP2-DPCs to treat cancer, TOP2-DPC lesions also can cause rearrangement of an organism’s genome that leads to cancer. If they are not removed, they trigger cell death. That led Williams and the research team to find out how DPCs are located and broken down. In his metaphor, the protein ZATT “is like a bomb-sniffing dog.” When it locates the target, it sounds an alarm to mobilize the recruitment of TOP2, which “cuts the red wire to disarm these threats.”

Schellenberg says, “We’ve discovered how we defend against this potent means of killing.” The knowledge may help researchers make drugs that kill cancer cells more effective.

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