An international team led by NIEHS scientists was 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 these crosslinks with the help of another protein, known as TDP2.
Because DPCs form when individuals receive certain cancer treatments, the new understanding of how TDP2 and ZATT work together to repair the damage may improve the health outcomes of cancer patients. The findings were published Sept. 29 in the journal Science.
Researchers knew that TDP2 was important for removing DPCs, but they did not know how the protein was directed to where it was needed, according to corresponding author Scott Williams, Ph.D. He is the deputy chief of the NIEHS Genome Integrity and Structural Biology Laboratory. Williams and his team used a multipronged approach to identify ZATT as a new contributor to this process and to determine how it guides TDP2 to DPCs so they can be repaired.
How DPCs form
To visualize how these proteins direct DPC repair, it helps to first understand how DPCs are created. Matthew Schellenberg, Ph.D., an NIEHS visiting fellow and lead author on the paper, said when DNA becomes tangled inside of cells, organisms use a protein called topoisomerase 2 (TOP2) to untangle it.
"Imagine your DNA is a giant ball of yarn," Schellenberg said. "TOP2 cuts and reties individual threads to disentangle the ball." 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 — 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 forms the stable TOP2-DPC complex and leads to the accumulation of severed DNA that kills cells.
Link to disease
Williams likened TOP2-DPCs to ticking time bombs for cells. He said these molecular charges are armed by interaction of TOP2 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 use to destroy cancer cells, making TOP2-DPCs double-edged swords, according to Williams. If they are not removed, they trigger cell death.
Although cancer drugs induce formation of TOP2-DPCs to treat cancer, TOP2-DPC lesions can also be the source of disease. These lesions can cause a rearrangement of an organism’s genome that leads to cancer. For this reason, Williams and his colleagues said it was necessary to learn how DPCs are located and broken down.
"In this study, we discovered a new molecular disarmament apparatus for these cell-killing bombs," Williams said. "ZATT is like a bomb sniffing dog, so when it locates its target, it sounds an alarm to mobilize the recruitment of TDP2, which cuts the red wire to disarm these threats."
Improving human health
Schellenberg said chemotherapeutic drugs, such as etoposide, are not the only pharmaceuticals that induce DPCs. Many antibiotics currently on the market use the same method to damage bacterial DNA. He said this work was part of a larger effort to figure out how researchers could use this key vulnerability to improve health.
"We’ve discovered how our bodies defend against this potent means of cell killing," Schellenberg said. "It is our hope that this information will enable development of new drugs that target these defenses. By lowering the defenses, we may make drugs that kill cancer cells more effective."
Citation: Schellenberg MJ, Lieberman JA, Herrero-Ruiz A, Butler LR, Williams JG, Munoz-Cabello AM, Mueller GA, London RE, Cortes-Ledesma F, Williams RS. 2017. ZATT (ZNF451)-mediated resolution of topoisomerase 2 DNA-protein cross-links. Science 357(6358):1412−1416.